JP2021524493A - Combination of PPAR agonist and p38 kinase inhibitor for the prevention or treatment of fibrotic disease - Google Patents

Abstract

The present invention is for use in methods of preventing or treating fibrotic diseases or disorders in a subject: (a) PPAR agonist; (b) p38 kinase inhibitor, and optionally; (c) one or more. With respect to a combination drug comprising a pharmaceutically acceptable diluent, additive or carrier. [Selection diagram] None

Description

The present invention relates to methods of preventing or treating fibrotic diseases or disorders.

Fibrotic disorders are often serious illnesses that result in loss of specific organ function and poor quality of life. In the United States, the prevalence of fibroproliferative disease is increasing due to population aging, as well as increased obesity and metabolic disorders. Approximately 45% of deaths in the United States are associated with the presence of one or more fibroproliferative disorders.

Fibrosis is associated with hyperaccumulation of the extracellular matrix (mainly composed of collagen) and usually loses function when normal tissue is replaced with acellular scar tissue. Fibrotic diseases often affect specific organs. Fibrotic diseases of the liver include cirrhosis of the liver, which can result from chronic hepatitis B or C infections, diabetes, obesity, autoimmune damage, and chronic exposure to toxins, including alcohol. Fibrotic disease of the kidney is the result of kidney damage and can contribute to renal failure. The presence of tubular interstitial fibrosis and glomerular fibrosis in the kidney affects chronic progressive renal disease and is considered to be the major mechanism leading to end-stage renal disease. The presence of type I and type II diabetes is generally the basis for the development of renal fibrosis. Chronic renal failure is often a sign of renal fibrosis and can be caused by exposure to chemicals and nephrotoxic drugs. In addition, genetic causes and infections can cause renal fibrosis. For example, fibrosis of heart tissue and its loss of function are caused by hypoxic and ischemic events that reduce blood flow and tissue oxidation. Cardiomyocytes can be fatal and can be replaced by fibrotic tissue.

For example, fibrotic diseases of the lung include interstitial lung diseases characterized by pneumonia and fibrosis. Such diseases of the lungs may have specific causes, including underlying vascular disease, sarcoidosis, Kay pneumonia or systemic scleroderma. However, in most cases the cause is unknown. Idiopathic pulmonary fibrosis is a rare but serious disorder of unknown cause. IPF is detected by various diagnoses that exclude other causes, such as those specified. Interstitial lung disease (ILD) is associated with dysfunction of the lungs due to fibrosis. Idiopathic pulmonary fibrosis (IPF) is a type of ILD that affects approximately 170,000 people in Europe and 130,000 people in the United States. IPF is a fatal disease with a median survival time of 3-5 years from diagnosis. Only less than 30% survive over 5 years. Until recently, none of the effective treatment options other than lung transplantation have been shown to be effective. The most common cause of death is respiratory failure due to progressive loss of lung function.

Recently, the receptor tyrosine kinase inhibitor nintedanib has been approved by the FDA to treat IPF. However, nintadenib is associated with serious systemic adverse events, including GI adverse reactions, liver enzyme improvement, loss of appetite, headache, weight loss and hypertension. Pirfenidone was also approved by the FDA in 2014 to treat IPF. The mechanism of action of pirfenidone in the treatment of IPF has not been established. Pirfenidone should be administered in high doses (801 mg) with meals three times daily. Pirfenidone also has serious side effects including nausea, rash, abdominal pain, upper respiratory tract infection, diarrhea, malaise, headache, dyspepsia, dizziness, vomiting, loss of appetite, gastroesophageal reflux disease and sinusitis. More importantly, both nintedanib and pirfenidone are only partially effective, reducing the rate of decline in lung function by only about 50%. Neither drug affects all-cause mortality in patients with IPF and does not improve quality of life.

Therefore, there is still a need for effective anti-fibrotic techniques for treating fibrotic diseases, particularly improving the efficacy and tolerability of treatments for pulmonary fibrotic diseases, including IPF.

Combination medications containing PPAR agonists such as pioglitazone and p38 inhibitors such as pamapimod and compounds of formula I or II as defined below herein are fibrotic diseases or disorders, especially pulmonary fibrotic such as IPF. It has now been unexpectedly found to be useful in preventing or treating the disease. In a standard model established in IPF studies, treatment with a combination drug of the invention achieves greater efficacy in reducing pulmonary fibrosis than treatment with a single PPAR agonist or p38 inhibitor, and oral delivery. It was surprisingly found that the improvement in efficacy and tolerability was achieved. In addition, the combination drug synergistically regulates the expression of interleukin / interleukin receptors, TNF / TNF receptors, and multiple inflammatory genes in the CC and CXX motif chemokine gene families. Unexpectedly, it was found to exhibit potentially potent anti-inflammatory effects not exhibited by either single drug.

Therefore, in the first aspect, the present invention is used in a method of preventing or treating a fibrotic disease or disorder in a subject, the following:
Provided are a combination drug comprising (a) a PPAR agonist (b) a p38 kinase inhibitor and optionally (c) one or more pharmaceutically acceptable diluents, additives or carriers.

In a further aspect, the invention is a kit for use in a method of preventing or treating a fibrotic disease or disorder in a subject.
Less than:
(A) PPAR agonist (b) p38 kinase inhibitor, and optionally (c) a combination drug comprising one or more pharmaceutically acceptable diluents, additives or carriers.
Provide the kit, including instructions for using the kit.

It is a graph which shows the lung weight normalized with respect to the body weight of an individual animal. Bleomycin infusion resulted in a significant increase in lung weight after normalization compared to sham control without bleomycin infusion. Substantially smaller post-normalized lung weights were observed in groups treated with either 25 mg / kg pioglitazone or 100 mg / kg pamapimod alone or in combination (Groups 3, 4 and 5 vs. Group 2). , P <0.05, t-test). It should be noted that this combination reduced lung weight after normalization to a greater extent than the positive control pirfenidone. It is a graph which shows the influence on the fibrosis score in each treatment group. Daily induction with 1.5 U / kg bleomycin followed by 200 μL of vehicle (Group 2) resulted in fairly high fibrosis and the highest group mean fibrosis index (4.8). Substantially lower fibrosis was present in the group treated with either 25 mg / kg pioglitazone or 100 mg / kg pamapimod alone or in combination, as indicated by the lower mean fibrosis index group (Group 3). 4, 5 pair group 2, P <0.05, t-test). The group with the lowest mean fibrosis index was present in group 5, indicating that the combination of pioglitazone and pamapimod was more effective in lowering the fibrosis score than either drug alone. It should be noted that this combination reduced the post-normalized fibrosis score to a greater extent than the positive control pirfenidone.

To interpret the specification, the following definitions apply, and whenever appropriate, the singular term may include more than one and vice versa. It should be understood that the terms used herein are for the purpose of describing a particular embodiment only and are not intended to be limiting.

The features, integers, properties, compounds, chemical moieties or groups described in connection with a particular aspect, embodiment or example of the invention are optional as described herein unless they are incompatible with them. It should be understood as applicable to other embodiments, embodiments or examples. All of the features disclosed herein (including all of the appended claims, abstracts and drawings) and / or all of the steps of any method or process so disclosed are this. Any combination may be combined, except for combinations in which at least a portion of such features and / or steps are mutually exclusive. The present invention is not limited to the details of any embodiment. The present invention is any novel one or any novel combination of features disclosed herein (including any of the appended claims, abstracts and drawings), or so disclosed. Deploy to any new one, or any new combination of steps of any method or process.

The terms "comprising," "having," and "inclusion" are interpreted as open-ended terms (ie, including, but not limited to, "unless otherwise specified. It should be.

The term "pharmaceutically acceptable diluent, additive or carrier" as used herein is used with humans and / or animals without excessive adverse side effects (such as toxicity, irritation and allergic reactions). A diluent, additive or carrier suitable for use, which is commensurate with a reasonable benefit / risk ratio. A "diluent" is an agent added to the bulk volume of an activator that constitutes a solid composition. As a result, the size of the solid composition increases, which makes it easier to handle. Diluents are useful when the dose of drug per solid composition is low and the solid composition is otherwise too small. The "additive" can be a binder, a lubricant, a flow accelerator, a coating additive or a combination thereof. Therefore, additives are intended to serve multiple purposes. The "carrier" can be a solvent, suspending agent or vehicle for delivering the compound to the subject.

The term "fibrotic disease or disorder" is intended to refer to a medical condition of the body known in the art associated with a disease or disorder caused by an organ that develops excess fibrotic connective tissue due to impaired function. There is. Thus, the term "fibrotic disease or disorder" is a disease selected from the group consisting of pulmonary fibrosis, hepatic fibrosis, renal fibrosis, myocardial fibrosis, ocular fibrosis or cutaneous fibrosis, but not limited to: Or intended to include disability.

The term "pulmonary fibrosis" refers to idiopathic pulmonary fibrosis (IPF), familial interstitial pulmonary fibrosis, nonspecific interstitial pneumonia (NSIP), unexplained organizing pneumonia (COP), sarcoidosis, Refers to a group of fibrotic diseases or disorders that affect the lungs, such as chronic obstructive pulmonary disease (COPD) and asthma. "Fibrotic disease or disorder affecting the lungs" or "fibrotic lung disease or disorder" are terms interchangeably used herein and are used interchangeably herein in progressive loss of lung function in lung tissue, primarily collagen. Refers to a respiratory disease in which scars are formed due to the accumulation of excess fibrotic connective tissue leading to. Accumulation of excess fibrotic connective tissue results in thickening of the alveolar wall, leading to diminished lung function. As a result, patients suffer from shortness of breath, are physically unable to breathe themselves, and are at risk for pneumonia or other serious lung infections. In some patients, a specific cause of the disease can be diagnosed, but in others, a problematic cause, a condition called idiopathic pulmonary fibrosis (IPF), cannot be determined. There is no treatment to reverse fibrosis or prevent further loss of lung function. Recently, the receptor tyrosine kinase inhibitor nintedanib has been approved by the FDA to treat IPF. However, nintadenib is associated with serious systemic adverse events, including GI adverse reactions, liver enzyme improvement, loss of appetite, headache, weight loss and hypertension. Pirfenidone was also approved by the FDA in 2014 to treat IPF. Pirfenidone also has serious side effects including nausea, rash, abdominal pain, upper respiratory tract infection, diarrhea, malaise, headache, dyspepsia, dizziness, vomiting, loss of appetite, gastroesophageal reflux disease and sinusitis. More importantly, both nintedanib and pirfenidone are only partially effective, reducing the rate of decline in lung function by only about 50%. Neither drug affects all-cause mortality in patients with IPF and does not improve quality of life.

The term "idiopathic pulmonary fibrosis (IPF)" refers to lung disease that occurs in middle-aged or elderly adults (the median age at diagnosis is 66 years and ranges from 55 to 75 years). IPF is confined to the lungs and is associated with histopathological or radiation patterns typical of normal interstitial pneumonia. The cause of IPF is unknown, but smoking history, genetic factors and environmental damage are thought to trigger pathological changes leading to fibrotic remodeling of lung tissue. After lung injury, epithelial cells release an inflammatory mediator that initiates an antifibrinolytic coagulation cascade, which induces platelet activation and thrombus formation. This is followed by the entry of white blood cells (eg, neutrophils, macrophages and T cells). The mobilized leukocytes secrete fibrotic progressive cytokines such as IL-1β, TNF-α and TGF-β. In subsequent stages, fibroblasts and myofibroblasts become epithelial cells that have undergone epithelial-mesenchymal transition, as well as bone marrow-derived fibroblasts, and resident fibroblasts that proliferate and differentiate into myofibroblasts. Derived from. These cells release collagen and other fibrotic components. IPF is a chronic, progressive, irreversible and ultimately lethal lung disease. Life expectancy after diagnosis ranges from 3 to 5 years.

The term "familial interstitial pulmonary fibrosis" is an IPF-like disease that affects two or more relatives. Familial interstitial pulmonary fibrosis has been suggested to be associated with changes in telomere length or genetic mutation.

The term "nonspecific interstitial pneumonia (NSIP)" refers to a disease caused by a response to certain medications, HIV, and other conditions. The disease is primarily characterized by inflammation of stromal cells. Fibrotic morphology is defined by thickening and scarring of lung tissue.

The term "unexplained organizing pneumonia (COP)" refers to a disease that has alveolar inflammatory changes similar to standard pneumonia and also involves bronchiolar involvement. Histologically, COP is a mild patchy interstitial inflammation without fibrosis, as well as blasts of granule tissue consisting of mononuclear cells, foamy macrophages, and fibrotic tissue (masson) in the distal airspace. ) Is characterized.

The term "sarcoidosis" refers to a disease associated with an abnormal collection of inflammatory cells into a mass called a granuloma. If sarcoidosis affects the lungs, there may be wheezing, coughing, shortness of breath or chest pain.

The term chronic obstructive pulmonary disease (COPD) refers to chronic inflammatory lung disease that causes airflow obstruction from the lungs. Symptoms include dyspnea, cough, mucus (sputum) production and wheezing.

The term "asbestosis" refers to a disease characterized by long-term inflammation and scarring of the lungs due to asbestosis exposure.

The term "pharmaceutically acceptable salt" of a compound means that it is a pharmaceutically acceptable salt and that the salt has the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; or acetic acid, propionic acid, hexanic acid, cyclopentanepropionic acid, glycol. Acids, pyruvate, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxy-benzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfone Acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4 -Methylbicyclo [2.2.2] -Octa-2-ene1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, laurylsulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, Acid addition salts formed with organic acids such as salicylic acid, stearic acid, muconic acid; or (2) acidic protons present in the parent compound are replaced by metal ions such as alkali metal ions, alkaline earth ions or aluminum ions. Includes salts formed either when used or when coordinated to an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine. Preferred salts include acid addition salts formed with hydrochloric acid.

The terms "subject" and "patient" are used interchangeably herein to refer to mammals, especially humans.

The term "about" as used herein refers to +/- 10% of a given measurement.

In a first aspect, the invention is used in a method of preventing or treating a fibrotic disease or disorder in a subject, the following:
Provided are (a) PPAR agonists (b) p38 kinase inhibitors, and optionally (c) a combination drug comprising one or more pharmaceutically acceptable diluents, additives or carriers.

PPAR agonist The term "PPAR agonist", as used herein, activates a peroxisome proliferator-activated receptor (PPAR) such as PPAR gamma receptor, PPAR alpha receptor, PPAR delta receptor or a combination thereof. PPAR gamma agonists (eg, pioglycazone, troglitazone, or rosiglitazone), PPAR alpha agonists (eg, bezafibrate, phenofibrate (phenofibric acid), fibrates such as clofibrate or gemfibrodil), PPAR dual. Activators (PPAR alpha / gamma or PPAR alpha / delta agonists) (eg, alegrita monkeys, muragrita monkeys, tesagrita monkeys, lagagrita monkeys, salogrita monkeys, GFT505 or nabegrita monkeys), PPAR delta agonists (eg GW501516), PPAR pan agonists (PPAR alpha / delta) / Gamma agonists) or selective PPAR modulators (eg INT131), and pharmaceutically acceptable salts of these compounds. Generally, PPAR gamma agonists, PPAR modulators, PPAR alpha agonists and / or PPAR alpha / gamma dual agonists are used in the combination reagents of the present invention, in particular PPAR gamma agonists, PPAR alpha agonists and / or PPAR alpha / gamma dual agonists. More specifically, PPAR gamma agonists and / or PPAR alpha agonists selected from the group consisting of pioglycazone, rosiglitazone, troglitazone, phenofibrate, bezafibrate and pharmaceutically acceptable salts thereof, and more specifically, A PPAR gamma agonist selected from the group consisting of pioglycazone, rosiglitazone, troglitazone and pharmaceutically acceptable salts thereof, preferably pioglitazone or a pharmaceutically acceptable salt thereof, is used in the combination drug of the present invention. .. The PPAR alpha agonists used in the combination pharmaceuticals of the present invention are bezafibrate, phenofibrate (phenofibric acid), clofibrate, gemfibrozil and pharmaceutically acceptable salts thereof, preferably bezafibrate, phenofibrate (phenofibric acid). ) Or those pharmaceutically acceptable salts, more preferably bezafibrozil or the pharmaceutically acceptable salts thereof. The PPAR alpha / gamma dual agonists used in the combinational medicaments of the present invention are allegritasal, muragritazar, tesagritazar, lagaglitasal, salogrita monkey, GFT505, nabegrita monkey and pharmaceutically acceptable salts thereof, preferably muragrita monkey, tesaglitazal or pharmaceutically acceptable. Selected from the group consisting of those salts that are acceptable. Preferably PPAR gamma agonists and / or PPAR alpha agonists are used in the combination drugs of the invention, more preferably pioglitazone, rosiglitazone, troglitazone, phenofibrate, bezafibrate, INT131 and pharmaceutically acceptable salts thereof. A PPAR gamma agonist or modulator and / or PPAR alpha agonist selected from the group consisting of, and even more preferably a PPAR gamma agonist selected from the group consisting of pioglitazone, rosiglitazone, troglitazone and pharmaceutically acceptable salts thereof. used. Even more preferably, pioglitazone or a pharmaceutically acceptable salt thereof, in particular pioglitazone hydrochloride, is used in the combination drug of the present invention.

In one embodiment, the thiazolidinedione PPAR agonist is used in the combination drug of the present invention. Suitable thiazolidinedione PPAR agonists are, for example, pioglitazone, troglitazone, rosiglitazone or pharmaceutically acceptable salts thereof. A particularly suitable thiazolidinone PPAR agonist is pioglitazone or a pharmaceutically acceptable salt thereof, in particular pioglitazone hydrochloride.

によって表される。 Pioglitazone is described, for example, in U.S. Pat. No. 4,687,777, or Dormandy JA, Chambernnel B, Eckland DJ, Erdmann E, Massi-Benedtti M, Moules IK, Skrhad. , Wilcox RG, Wilhelmsen L, Betteridge J, Birkeland K, Goray A, Heine RJ, Koranyi L, Laakso M, Mokan M, Norkus A, Pioglitazone, Pioglitazone, Pioglitazone J, Smith U, Tuton J; PROactive investigator, Lancet. October 8, 2005; Volume 366 (No. 9493): Structural formulas described in pages 1279-89 and shown below:

Represented by.

によって表される。 Troglitazo is, for example, Florez JC, Jabronski KA, Sun MW, Bayley N, Kahn SE, Shamoon H, Hamman RF, Knowler WC, Nathan DM, Altshuller D; Diabetes Research. J Clin Endocrinol Metab. April 2007; Volume 92 (No. 4): Described on pages 1502-9 and the structural formula shown below:

Represented by.

によって表される。 Rosiglitazone is described, for example, by Nissen SE, Wolski K. et al. N Engl J Med. June 14, 2007; Volume 356 (No. 24): pp. 2457-71 (N Engl J Med. July 5, 2007; Volume 357 (No. 1): Typographical error on page 100). Phenofibrate is, for example, Bonds DE, Craven TE, Buse J, Clause JR, Cuddyhy R, Elam M, Ginsberg HN, Kirchner K, Marcovina S, Peach John JC, O'Connor Diabetologia. June 2012; Volume 55 (No. 6): pp. 1641-50, structural formula shown below:

Represented by.

によって表される。 Bezafibrate is, for example, I.I. Goldenberg, M.D. Benderly, U.S.A. Goldbourt, Vascural health and risk management. 2008, Volume 4 (No. 1): Described on pages 131-141, and the structural formula shown below:

Represented by.

によって表される。 Crofibrate is described, for example, by Rabkin SW, Hayden M, Frohlic J. et al. Atherosclerosis. October 1988; Volume 73 (No. 2-3): Described on pages 233-40 and the structural formula shown below:

Represented by.

によって表される。 Phenofibrate (phenofibric acid) is available, for example, from Schima SM, Maciejewski SR, Hilleman DE, Williams MA, Maurice hilleman SM. Expert Opin Pharmacother. April 2010; Volume 11 (No. 5): Described on pages 731-8, and the structural formula shown below:

Represented by.

によって表される。 Gemfibrozil is, for example, Adamag AS, Mithani S, Al Allol B, Cholesterol D, Bertog S, Bloomfield HE; Veterans Affairs High-Density Lipoprotein Am Heart J. May 2009; Volume 157 (No. 5): Structural formulas described on pages 913-8 and shown below:

Represented by.

によって表される。 Allegritasal are, for example, Lincoff AM, Tardef JC, Schwartz GG, Nichols SJ, Ryden L, Neal B, Malmberg K, Wedel H, Buse JB, Henry RR, Weichert A, Can AleCardio researcher. JAMA. April 16, 2014; Volume 311 (No. 15): pp. 515-25, structural formula shown below:

Represented by.

によって表される。 Muragrita monkeys include, for example, Fernandez M, Gastaldelli A, Triplit C, Hardies J, Casolaro A, Petz R, Tantiwong P, Musi N, Cersosimo E, Ferranini E, D. Diabetes Obes Metab. October 2011; Volume 13 (No. 10): Structural formulas described on pages 893-902 and shown below:

Represented by.

によって表される。 Tesagrita monkeys are described, for example, by Bays H, McElhattan J, Brizinski BS; GALLANT6 research group. Diab Vasc Dis Res. September 2007; Volume 4 (No. 3): Described on pages 181-93, and the structural formula shown below:

Represented by.

によって表される。 Ragagrita monkeys are described, for example, by Saad MF, Greco S, Osei K, Lewin AJ, Edwards C, Nunes M, Reinhardt RR; Ragaglitazar Dose-Ranging Research Group, Diabetes Care. June 2004; Vol. 27 (No. 6): Described on pages 1324-9, and the structural formula shown below:

Represented by.

によって表される。 Salogrita monkeys are described, for example, by Agraval R. et al. Curr Drag Targets. February 2014; Volume 15 (No. 2): Described on pages 151-5, and the structural formula shown below:

Represented by.

によって表される。 Nabegrita monkeys are described, for example, by Ahlawat P, Srinivas NR. Eur J Drug Metabolism and Pharmacokinet. July-September 2008; Volume 33 (No. 3): pp. 187-90. GW501516 is, for example, Wang X, Sng MK, Foo S, Chong HC, Lee WL, Tang MB, Ng KW, Luo B, Chong C, Wong MT, Tong BM, Chiba S, Loo SC, Zh. J Control Release. January 10, 2015; Volume 197, pp. 138-47, structural formula shown below:

Represented by.

によって表される。 GFT505 is described, for example, in Cario B, Staels B. et al. Expert Opin Investig Drugs. October 2014; Volume 23 (No. 10): pp. 1441-8, structural formula shown below:

Represented by.

によって表される。 INT131 includes, for example, Daygerly JP, McGee LR, Rubenstein SM, House JB, Cushing TD, Li Y, Motani A, Chen JL, Frans Timmermans W, Ye G, Learn Men Keyare P, Frans Timmerman H, Beckmann H, Weiszmann J, Lindstrom M, Walker N, Liu J, Biermann D, Wang Z, Hagiwara A, Iida T, Aramaki Hi .. Bioorg Med Chem. February 15, 2013; Volume 21 (No. 4): pp. 979-92, structural formula shown below:

Represented by.

PPAR activation with PPAR agonists is usually potent in the range of low nanomolar to low micromolar concentrations, eg, 0.1 nM to 100 μM. In some embodiments, the PPAR activation is weak or partial, i.e. the PPAR agonist is used in the methods of the invention and causes maximum PPAR activation in a 10% to 100% reporter assay system. It results in maximal activation of PPAR receptors as compared to known reference PPAR agonists.

p38 Kinase Inhibitors The terms "p38 kinase inhibitor" or "p38 inhibitor", both used interchangeably herein, are p38-alpha (MAPK14), p38-beta (MAPK11), p38-gamma. Refers to drugs that inhibit p38 mitogen-activating protein (MAP) kinases such as (MAPK12 / ERK6) and / or p38-delta (MAPK13 / SAPK4). Examples of p38 inhibitors include compounds of formulas I and II as defined herein, as well as pharmaceutically acceptable salts thereof. Further examples of p38 inhibitors include pamapimod, akumapimod, rosmapimod, dilmapimod, semapimod, AZD7624, ARRY-371797, LY22282820, R9111, PH-779804, BIRB796, VX-702, VX-745, SB239063S. , And their pharmaceutically acceptable salts.

In one embodiment, the combination drug according to the invention is:
(A) PPAR agonist (b) p38 kinase inhibitor, and optionally (c) one or more pharmaceutically acceptable diluents, additives or carriers.
The p38 inhibitor inhibits p38-alpha, p38-beta, p38-gamma or p38-delta, or a combination thereof, preferably p38-alpha and / or p38-beta, more preferably p38-. Inhibits alpha.

［式中、
Ｚは、ＮまたはＣＨであり、
Ｗは、ＮＲ^２であり、
Ｘ^ｌは、Ｏ、ＮＲ^４（式中、Ｒ^４は、水素またはアルキルである）、ＳまたはＣＲ^５Ｒ^６（式中、Ｒ^５およびＲ^６は、独立して水素またはアルキルである）またはＣ＝Ｏであり、
Ｘ^２は、ＯまたはＮＲ^７であり、
Ａｒ^１は、アリールまたはヘテロアリールであり、
Ｒ^２は、水素、アルキル、アシル、アルコキシカルボニル、アリールオキシカルボニル、ヘテロアルキルカルボニル、ヘテロアルキルオキシカルボニル、または−Ｒ^２１−Ｒ^２２（式中、Ｒ^２１は、アルキレンまたは−Ｃ（＝Ｏ）−であり、Ｒ^２２は、アルキルまたはアルコキシである）であり、
Ｒ^１は、水素、アルキル、ハロアルキル、アリール、アラルキル、ヘテロアリール、ヘテロアラルキル、シクロアルキル、シクロアルキルアルキル、ヘテロアルキル置換シクロアルキル、ヘテロ置換シクロアルキル、ヘテロアルキル、シアノアルキル、ヘテロシクリル、ヘテロシクリルアルキル、Ｒ^１２−ＳＯ_２−ヘテロシクロアミノ（式中、Ｒ^１２は、ハロアルキル、アリール、アラルキル、ヘテロアリールまたはヘテロアラルキルである）、−Ｙ^１−Ｃ（Ｏ）−Ｙ^２−Ｒ^１１（式中、Ｙ^１およびＹ^２は、独立して、存在しないまたはアルキレン基のどちらかであり、Ｒ^１１は、水素、アルキル、ハロアルキル、ヒドロキシ、アルコキシ、アミノ、モノアルキルアミノまたはジアルキルアミノである）、（ヘテロシクリル）（シクロアルキル）アルキルまたは（ヘテロシクリル）（ヘテロアリール）アルキルであり、
Ｒ^３は、水素、アルキル、シクロアルキル、シクロアルキルアルキル、アリール、アラルキル、ハロアルキル、ヘテロアルキル、シアノアルキル、アルキレン−Ｃ（Ｏ）−Ｒ^３１（式中、Ｒ^３１は、水素、アルキル、ヒドロキシ、アルコキシ、アミノ、モノアルキルアミノまたはジアルキルアミノである）、アミノ、モノアルキルアミノ、ジアルキルアミノまたはＮＲ^３２−Ｙ^３−Ｒ^３３（式中、Ｙ^３は、−Ｃ（Ｏ）、−Ｃ（Ｏ）Ｏ−、−Ｃ（Ｏ）ＮＲ^３４、Ｓ（Ｏ）_２またはＳ（Ｏ）_２ＮＲ^３５であり、Ｒ^３２、Ｒ^３４およびＲ^３５は、独立して、水素またはアルキルであり、Ｒ^３３は、水素、アルキル、シクロアルキル、シクロアルキルアルキル、ヘテロアルキルまたは置換されていてもよいフェニルである）またはアシルであり、
Ｒ^７は、水素またはアルキルであり、
Ｒ^８およびＲ^９は、独立して、水素、アルキル、アリール、アラルキル、シクロアルキル、シクロアルキルアルキル、ヘテロアルキル、アルキルスルホニル、アリールスルホニル、−Ｃ（Ｏ）−Ｒ^８ｌ（式中、Ｒ^８１は、アルキル、アリール、アラルキル、シクロアルキル、シクロアルキルアルキル、ヘテロアルキル、アルコキシ、アリールオキシ、アミノ、モノまたはジアルキルアミノ、アリールアミノまたはアリール（アルキル）アミノである）であるか、またはＲ^８とＲ^９は一緒になって、＝ＣＲ^８２Ｒ^８３（式中、Ｒ^８２およびＲ^８３は、独立して、水素、アルキル、シクロアルキル、シクロアルキルアルキルまたは置換されていてもよいフェニルである）を形成する］
の化合物または薬学的に許容されるその塩、および任意選択で１種または複数の薬学的に許容される希釈剤、添加物または担体である。 In a further embodiment, the p38 inhibitor for use in the combination drug according to the invention is of formula I or II.

[During the ceremony,
Z is N or CH,
W is NR ²
X ^l is O, NR ⁴ (in the formula, R ⁴ is hydrogen or alkyl), S or CR ⁵ R ⁶ (in the formula, R ⁵ and R ⁶ are independently hydrogen or alkyl) or C = O,
X ² is O or NR ⁷ and
Ar ¹ is aryl or heteroaryl and
R ² is hydrogen, alkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, heteroalkylcarbonyl, heteroalkyloxycarbonyl, or -R ^21- R ²² (in the formula, R ²¹ is alkylene or -C (= O)-. And R ²² is alkyl or alkoxy)
R ¹ is hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl-substituted cycloalkyl, hetero-substituted cycloalkyl, heteroalkyl, cyanoalkyl, heterocyclyl, heterocyclylalkyl, R. ^12- SO ₂ -heterocycloamino (in the formula, R ¹² is haloalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl ^{), -Y 1-} C (O) -Y ^2- R ¹¹ (in the formula, Y ¹ and Y ² are independently either absent or alkylene groups, and R ¹¹ is hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino), (heterocyclyl). (Cycloalkyl) alkyl or (heterocyclyl) (heteroaryl) alkyl,
R ³ is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, haloalkyl, heteroalkyl, cyanoalkyl, alkylene-C (O) -R ³¹ (in the formula, R ³¹ is hydrogen, alkyl, hydroxy, Alkoxy, amino, monoalkylamino or dialkylamino), amino, monoalkylamino, dialkylamino or NR ^32- Y ^3- R ³³ (in the formula, Y ³ is -C (O), -C (O). O-, -C (O) NR ³⁴ , S (O) ₂ or S (O) ₂ NR ³⁵ , R ³² , R ³⁴ and R ³⁵ are independently hydrogen or alkyl and R ³³ is , Hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl or optionally substituted phenyl) or acyl,
R ⁷ is hydrogen or alkyl
R ⁸ and R ⁹ are independently hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, alkylsulfonyl, arylsulfonyl, -C (O) -R ^8l (in the formula, R ⁸¹ is , Alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, alkoxy, aryloxy, amino, mono or dialkylamino, arylamino or aryl (alkyl) amino), or R ⁸ and R ⁹ Together form = CR ⁸² R ⁸³ (in the formula, R ⁸² and R ⁸³ are independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl or optionally substituted phenyl). ]
Compounds or pharmaceutically acceptable salts thereof, and optionally one or more pharmaceutically acceptable diluents, additives or carriers.

［式中、
Ｚは、ＮまたはＣＨであり、
Ｗは、ＮＲ^２であり、
Ｘ^ｌは、Ｏ、ＮＲ^４（式中、Ｒ^４は、水素またはアルキルである）、ＳまたはＣＲ^５Ｒ^６（式中、Ｒ^５およびＲ^６は、独立して水素またはアルキルである）またはＣ＝Ｏであり、
Ｘ^２は、ＯまたはＮＲ^７であり、
Ａｒ^１は、アリールまたはヘテロアリールであり、
Ｒ^２は、水素、アルキル、アシル、アルコキシカルボニル、アリールオキシカルボニル、ヘテロアルキルカルボニル、ヘテロアルキルオキシカルボニル、または−Ｒ^２１−Ｒ^２２（式中、Ｒ^２１は、アルキレンまたは−Ｃ（＝Ｏ）−であり、Ｒ^２２は、アルキルまたはアルコキシである）であり、
Ｒ^１は、水素、アルキル、ハロアルキル、アリール、アラルキル、ヘテロアリール、ヘテロアラルキル、シクロアルキル、シクロアルキルアルキル、ヘテロアルキル置換シクロアルキル、ヘテロ置換シクロアルキル、ヘテロアルキル、シアノアルキル、ヘテロシクリル、ヘテロシクリルアルキル、Ｒ^１２−ＳＯ_２−ヘテロシクロアミノ（式中、Ｒ^１２は、ハロアルキル、アリール、アラルキル、ヘテロアリールまたはヘテロアラルキルである）、−Ｙ^１−Ｃ（Ｏ）−Ｙ^２−Ｒ^１１（式中、Ｙ^１およびＹ^２は、独立して、存在しないまたはアルキレン基のどちらかであり、Ｒ^１１は、水素、アルキル、ハロアルキル、ヒドロキシ、アルコキシ、アミノ、モノアルキルアミノまたはジアルキルアミノである）、（ヘテロシクリル）（シクロアルキル）アルキルまたは（ヘテロシクリル）（ヘテロアリール）アルキルであり、
Ｒ^３は、水素、アルキル、シクロアルキル、シクロアルキルアルキル、アリール、アラルキル、ハロアルキル、ヘテロアルキル、シアノアルキル、アルキレン−Ｃ（Ｏ）−Ｒ^３１（式中、Ｒ^３１は、水素、アルキル、ヒドロキシ、アルコキシ、アミノ、モノアルキルアミノまたはジアルキルアミノである）、アミノ、モノアルキルアミノ、ジアルキルアミノまたはＮＲ^３２−Ｙ^３−Ｒ^３３（式中、Ｙ^３は、−Ｃ（Ｏ）、−Ｃ（Ｏ）Ｏ−、−Ｃ（Ｏ）ＮＲ^３４、Ｓ（Ｏ）_２またはＳ（Ｏ）_２ＮＲ^３５であり、Ｒ^３２、Ｒ^３４およびＲ^３５は、独立して、水素またはアルキルであり、Ｒ^３３は、水素、アルキル、シクロアルキル、シクロアルキルアルキル、ヘテロアルキルまたは置換されていてもよいフェニルである）またはアシルであり、
Ｒ^７は、水素またはアルキルである］
の化合物または薬学的に許容されるその塩および任意選択で、１種または複数の薬学的に許容される希釈剤、添加物または担体である。 In a preferred embodiment, the p38 inhibitor for use in the combination drug according to the invention is Formula I.

[During the ceremony,
Z is N or CH,
W is NR ²
X ^l is O, NR ⁴ (in the formula, R ⁴ is hydrogen or alkyl), S or CR ⁵ R ⁶ (in the formula, R ⁵ and R ⁶ are independently hydrogen or alkyl) or C = O,
X ² is O or NR ⁷ and
Ar ¹ is aryl or heteroaryl and
R ² is hydrogen, alkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, heteroalkylcarbonyl, heteroalkyloxycarbonyl, or -R ^21- R ²² (in the formula, R ²¹ is alkylene or -C (= O)-. And R ²² is alkyl or alkoxy)
R ¹ is hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl-substituted cycloalkyl, hetero-substituted cycloalkyl, heteroalkyl, cyanoalkyl, heterocyclyl, heterocyclylalkyl, R. ^12- SO ₂ -heterocycloamino (in the formula, R ¹² is haloalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl ^{), -Y 1-} C (O) -Y ^2- R ¹¹ (in the formula, Y ¹ and Y ² are independently either absent or alkylene groups, and R ¹¹ is hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino), (heterocyclyl). (Cycloalkyl) alkyl or (heterocyclyl) (heteroaryl) alkyl,
R ³ is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, haloalkyl, heteroalkyl, cyanoalkyl, alkylene-C (O) -R ³¹ (in the formula, R ³¹ is hydrogen, alkyl, hydroxy, Alkoxy, amino, monoalkylamino or dialkylamino), amino, monoalkylamino, dialkylamino or NR ^32- Y ^3- R ³³ (in the formula, Y ³ is -C (O), -C (O). O-, -C (O) NR ³⁴ , S (O) ₂ or S (O) ₂ NR ³⁵ , R ³² , R ³⁴ and R ³⁵ are independently hydrogen or alkyl and R ³³ is , Hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl or optionally substituted phenyl) or acyl,
R ⁷ is hydrogen or alkyl]
Compound or pharmaceutically acceptable salt thereof and optionally one or more pharmaceutically acceptable diluents, additives or carriers.

In a further embodiment, the p38 inhibitor for use in the combination drug according to the invention ^{is either X 1} with NR ⁴ and X ² with NR ⁷ , or X ¹ and X ² with O and R, respectively. ⁴ and R ⁷ are compounds of formula I, as defined above.

In a further embodiment, the p38 inhibitor for use in the combination drug according to the invention is X ¹ is NR ⁴ or O, X ² is NR ⁷ or O, and R ⁴ and R ⁷ are defined above. It is a compound of formula I, as it is said.

In a further embodiment, the p38 inhibitors for use in the combinatorial drug according to the invention are W is NR ² and R ² is hydrogen, alkyl, heteroalkyl, acyl or alkoxycarbonyl, preferably hydrogen or alkyl. A compound of formula I, preferably hydrogen.

In a further embodiment, p38 inhibitors for use in combination medicament according to the present invention, R ¹ is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl substituted cycloalkyl, heterosubstituted cycloalkyl, heteroalkyl , Cyanalkyl, heterocyclyl, heterocyclylalkyl or (heterocyclyl) (cycloalkyl) alkyl, a compound of formula I.

In a preferred embodiment, the p38 inhibitor for use in the combination drug according to the invention is ^{a compound of formula I, where R 2} is hydrogen and R ¹ is heteroalkyl or vice versa.

In a further embodiment, p38 inhibitors for use in combination medicament according to the present invention, R ¹ is hydrogen, alkyl, haloalkyl, heteroalkyl or cyano alkyl, a compound of formula I.

In a further embodiment, p38 inhibitors for use in combination medicament according to the present invention, R ¹ is cycloalkyl, cycloalkylalkyl, heteroalkyl substituted cycloalkyl, heterosubstituted cycloalkyl, heterocyclyl, heterocyclylalkyl, or (heterocyclyl) A compound of formula I that is (cycloalkyl) alkyl.

In a preferred embodiment, the p38 inhibitors for use in the combination drug according to the invention are R ¹ and R ² from hydrogen and hydroxyalkyl, respectively, preferably hydrogen, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl. , 3-Hydroxypropyl, 1- (Hydroxymethyl) -2-methylpropyl, 2-Hydroxybutyl, 3-Hydroxybutyl, 4-Hydroxybutyl, 2,3-Dihydroxypropyl, 2-Hydroxy-1-hydroxymethylethyl, From 2,3-dihydroxybutyl, 3,4-dihydroxybutyl, 2- (hydroxymethyl) -3-hydroxypropyl, 3-hydroxy-1- (2-hydroxyethyl) -propyl and 2-hydroxy-1-methylethyl , More preferably hydrogen, 2-hydroxyethyl, 2,3-dihydroxypropyl and 1- (hydroxymethyl) 2-hydroxyethyl, most preferably hydrogen, 2-hydroxy-propyl, 3-hydroxy-1- (2-). A compound of formula I, independently selected from hydroxyethyl) -propyl and 2-hydroxy-1-methylethyl.

In a further embodiment, p38 inhibitors for use in combination medicament according to the present invention, R ³ is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heteroalkyl, cyanoalkyl, alkylene -C (O) - A compound of formula I, which is R ³¹ (in the formula, R ³¹ is hydrogen, alkyl, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino) or acyl.

In a further embodiment, p38 inhibitors for use in combination medicament according to the present invention, R ³ is hydrogen, alkyl, haloalkyl, heteroalkyl, cyanoalkyl, cycloalkyl or cycloalkylalkyl, with a compound of formula I be.

In a further embodiment, p38 inhibitors for use in combination medicament according to the present invention, R ³ is hydrogen, alkyl, haloalkyl, heteroalkyl or cyano alkyl, a compound of formula I.

In a further embodiment, p38 inhibitors for use in combination medicament according to the present invention, R ³ is cycloalkyl or cycloalkylalkyl, which is a compound of formula I.

In a further embodiment, the p38 inhibitor for use in the combination drug according to the invention is a compound of formula I in which both ^{X 1} and X ^{2 are O.}

In a further embodiment, p38 inhibitors for use in combination medicament according to the present invention, R ¹ is alkyl or heteroalkyl, a compound of formula I.

In a further embodiment, p38 inhibitors for use in combination medicament according to the present invention, ^{R 1} is heteroalkyl, preferably 3-hydroxy-1- (2-hydroxyethyl) - propyl or 2-hydroxy-1- A compound of formula I, methyl ethyl.

In a further embodiment, p38 inhibitors for use in combination medicament according to the present invention, R ³ is an alkyl or heteroalkyl, a compound of formula I.

In a further embodiment, p38 inhibitors for use in combination medicament according to the present invention, ^{R 3} is alkyl, are preferably C1~C5 alkyl, more preferably C1~C4 alkyl, more preferably C1~C3 alkyl , A compound of formula I. In a particularly preferred embodiment, R ³ is ethyl or methyl, preferably methyl.

In a further embodiment, p38 inhibitors for use in combination medicament according to the present invention, R ³ is heteroalkyl, preferably 2-hydroxy - propyl, the compounds of formula I.

In a further embodiment, the p38 inhibitor for use in the combination drug according to the invention is a compound of formula I where W is NH.

In a further embodiment, the p38 inhibitor for use in the combination drug according to the invention is a compound of formula I, where Z is N.

In a further embodiment, the p38 inhibitor for use in the combinatorial drug according to the invention is ^{phenyl, most preferably Ar 1} which may be substituted with aryl, preferably one, two or three halo substituents. Is a compound of formula I, which is a phenyl substituted with two halo substituents at the ortho and para positions. In a particularly preferred embodiment, Ar ¹ is 2,4-difluorophenyl.

In a further embodiment, the p38 inhibitor for use in the combination drug according to the invention ^{is either X 1} with NR ⁴ and X ² with NR ⁷ , or X ¹ and X ² with O and R, respectively. ⁴ and R ⁷ are as defined above,
R ¹ is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl-substituted cycloalkyl, hetero-substituted cycloalkyl, heteroalkyl, cyanoalkyl, heterocyclyl, heterocyclylalkyl or (heterocyclyl) (cycloalkyl) alkyl.
R ³ is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heteroalkyl, cyanoalkyl, alkylene-C (O) -R ³¹ (in the formula, R ³¹ is hydrogen, alkyl, hydroxy, alkoxy, amino, Monoalkylamino or dialkylamino) or acyl,
W is NR ² and R ² is hydrogen, alkyl, acyl or alkoxycarbonyl.
Ar ¹ is aryl,
Z is N,
It is a compound of formula I.

In a preferred embodiment, the p38 inhibitors for use in the combination drug according to the invention are X ¹ and X ² , respectively O, Z, NH, W, NH, and Ar ^1. A compound of formula I that is a phenyl that may be substituted with two or three halo substituents, where R ¹ is heteroalkyl and R ^{3 is alkyl or heteroalkyl.}

［式中、Ａｒ^１、Ｗ、Ｘ^１、Ｚ、Ｒ^１、Ｒ^８およびＲ^９は、上の実施形態のいずれかにおいて定義されている通りである］
の化合物または薬学的に許容されるその塩である。 In a further embodiment, the p38 inhibitor for use in the combination drug according to the invention is Formula II.

[In the formula, Ar ¹ , W, X ¹ , Z, R ¹ , R ⁸ and R ⁹ are as defined in any of the above embodiments]
Compound or a pharmaceutically acceptable salt thereof.

Unless otherwise specified, the following terms have the meanings set forth below:
"Acyl" means a -C (O) R radical, where R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl, and alkyl, cycloalkyl, cycloalkylalkyl and phenylalkyl are As defined herein. Representative examples include, but are not limited to, formyl, acetyl, silcohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl and the like.

"Acylamino" means -NR'C (O) R radical, R'is hydrogen or alkyl, R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl, alkyl , Cycloalkyl, cycloalkylalkyl and phenylalkyl are as defined herein. Representative examples include, but are not limited to, formylamino, acetylamino, silcohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino, benzylcarbonylamino and the like.

"Alkoxy" means a -OR radical in which R is an alkyl as defined herein. Examples are methoxy, ethoxy, propoxy, butoxy and the like.

"Alkoxycarbonyl" means an ROC (O) -radical in which R is an alkyl as defined herein.

"Alkyl" means a monovalent linear saturated hydrocarbon radical consisting of 1 to 6 carbon atoms or a monovalent branched saturated hydrocarbon radical consisting of 3 to 6 carbon atoms. Examples include methyl, ethyl, propyl, 2-propyl, n-butyl, iso-butyl, tert-butyl, pentyl and the like. C1-C3 alkyl groups, especially ethyl and methyl, are preferred.

"Alkylsulfonyl" means RS (O) ₂ -radical, where R is the alkyl defined herein.

"Alkylene" means a divalent linear saturated hydrocarbon radical consisting of 1 to 6 carbon atoms or a divalent branched saturated hydrocarbon radical consisting of 3 to 6 carbon atoms. Examples are methylene, ethylene, 2,2-dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene and the like.

"Alkoxy" is alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, Y-C (O) -R (in the formula, Y is an absent or alkylene group and R is hydrogen, alkyl, haloalkyl, haloalkoxy. , Hydroxy, alkoxy, amino, monoalkylamino or dialkylamino), heteroalkyl, heteroalkyloxy, heteroalkylamino, halo, nitro, cyano, amino, monoalkylamino, dialkylamino, alkylsulfonylamino, heteroalkylsulfonyl Independent by one or more substituents, preferably one, two or three substituents, preferably selected from the group consisting of amino, sulfonamide, methylenedioxy, ethylenedioxy, heterocyclyl or heterocyclylalkyl. Means monovalent monocyclic or bicyclic aromatic hydrocarbon radicals which may be substituted with. The above-mentioned optionally substituted monocyclic aryl group is preferable. More specifically, the term aryl refers to alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, Y-C (O) -R (where Y is absent or an alkylene group and R is hydrogen. Alkoxy, haloalkyl, haloalkoxy, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino), heteroalkyl, heteroalkyloxy, heteroalkylamino, halo, nitro, cyano, amino, monoalkylamino, dialkylamino, alkyl Alkoxyamino, heteroalkylsulfonylamino, sulfonamide, methylenedioxy, ethylenedioxy, heterocyclyl and heterocyclylalkyl, preferably independently substituted with one, two or three substituents selected from the group. May include, but are not limited to, phenyl. Particularly preferred aryl groups are substituted phenyl groups selected from the group consisting of chlorophenyl, methoxyphenyl, 2-fluorophenyl, 2,4-difluorophenyl, 1-naphthyl and 2-naphthyl.

"Arylsulfonyl" means an RS (O) ₂ -radical in which R is an aryl as defined herein.

"Aralkyl" refers to an aryl group as defined herein, eg, benzyl, which is directly attached via an alkylene group.

"Aryloxy" means a -OR radical, such as phenoxy, where R is the aryl defined herein.

"Aryloxycarbonyl" means an RC (= O) -radical in which R is aryloxy, such as phenoxycarbonyl.

"Cycloalkyl" is a monovalent saturated cyclic hydrocarbon radical consisting of 3 to 7 ring carbons, more specifically listed in the included tables or described in Examples. Refers to a monovalent saturated cyclic hydrocarbon radical of a specific compound. These radicals can also be grouped within groups containing only such radicals, but within groups to which the first or second priority has been applied, or both. It can be divided and is understood to be, for example, cyclopropyl, cyclobutyl, cyclohexyl, 4-methyl-cyclohexyl and the like.

"Cycloalkylalkyl", R ^a is an alkylene group, R ^b is, -R ^a R ^b radicals is a cycloalkyl group as defined herein, means for example cyclohexyl-methyl.

A "substituted cycloalkyl" is a cyano or -Y-C (O) R (in the formula, Y is an absent or alkylene group, where R is hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, amino, monoalkylamino. , Dialkylamino or optionally substituted phenyl), as defined herein, having one, two or three (preferably one) ring hydrogen atoms. Cycloalkyl radicals, or more particularly cycloalkyl radicals of the specific compounds listed in the included tables or listed in the Examples.

"Halo" means fluoro, chloro, bromo or iodine, preferably fluoro and chloro.

"Haloalkyl" means an alkyl substituted with one or more identical or different halogen atoms, such as -CH ₂ Cl, -CF ₃ , -CH ₂ CF ₃ , -CH ₂ CCl _{3, and the} like.

"Heteroalkyl" means an alkyl radical as defined herein, with the understanding that the bonding point of a heteroalkyl radical is via a carbon atom, one, two or three hydrogens. If the atom is -OR ^a , -N (O) _n R ^b R ^c (in the formula, n is ^{0 or if both R b} and R ^c are independently alkyl, cycloalkyl or cycloalkylalkyl. Replaced by a radical selected independently from the group consisting of 1 and otherwise 0) and −S (O) _n R ^d (where n is an integer from 0 to 2). ^Ra is hydrogen, acyl, alkoxycarbonyl, alkyl, cycloalkyl or cycloalkylalkyl, and ^Rb and ^Rc are independent of each other, hydrogen, acyl, alkoxycarbonyl, alkyl, cycloalkyl, Cycloalkylalkyl, alkylsulfonyl, aminosulfonyl, monoalkyl or dialkylaminosulfonyl, aminoalkyl, mono or dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkylsulfonyl or alkoxyalkylsulfonyl, where n is 0, R ^d is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl or optionally substituted phenyl, and if n is 1 or 2, R ^d is alkyl, cycloalkyl, cycloalkylalkyl, substituted. May be phenyl, amino, acylamino, monoalkylamino or dialkylamino. Preferred heteroalkyl groups include hydroxyalkyl groups, preferably C1-C6 hydroxyalkyl groups. Representative examples are, but are not limited to, 2-hydroxyethyl, 2-hydroxy-propyl, 3-hydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2-hydroxy-1-methylethyl, 2,3- Dihydroxypropyl, 1-hydroxymethylethyl, 3-hydroxybutyl, 2,3-dihydroxybutyl, 2-hydroxy-1-methylpropyl, 3-hydroxy-1- (2-hydroxyethyl) -propyl, 2-aminoethyl, Includes 3-aminopropyl, 2-methylsulfonylethyl, aminosulfonylmethyl, aminosulfonylethyl, aminosulfonylpropyl, methylaminosulfonylmethyl, methylaminosulfonylethyl, methylaminosulfonylpropyl and the like. Particularly preferred heteroalkyl groups are 2-hydroxy-propyl, 3-hydroxy-1- (2-hydroxyethyl) -propyl or 2-hydroxy-1-methylethyl.

"Hydroxyalkyl" means an alkyl radical as defined herein that is substituted with one or more, preferably one, two or three hydroxy groups, provided that the same carbon atom is present. The condition is that it does not have more than one hydroxy group. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1- (hydroxymethyl) -2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl. , 4-Hydroxybutyl, 2,3-dihydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl, 2- (hydroxymethyl) -3-hydroxypropyl, 3 -Hydroxy-1- (2-hydroxyethyl) -propyl and 2-hydroxy-1-methylethyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl and 1- (hydroxymethyl) 2-hydroxyethyl, more preferably Includes 2-hydroxy-propyl, 3-hydroxy-1- (2-hydroxyethyl) -propyl and 2-hydroxy-1-methylethyl. Therefore, as used herein, the term "hydroxyalkyl" is used to define a subset of heteroalkyl groups.

"Heteroalkylcarbonyl" means ^{a Ra-} C (= O) -group in ^{which Ra} is a heteroalkyl group. Representative examples include acetyloxymethylcarbonyl, aminomethylcarbonyl, 4-acetyloxy-2,2-dimethyl-butane-2-oil, 2-amino-4-methyl-pentane-2-oil and the like.

"Heteroalkyloxy" ^{means a Ra-} O-group in which ^Ra is a heteroalkyl group. Representative examples include Me-C (= O) -O-CH _2- O- and the like.

"Heteroalkyloxycarbonyl" means ^{a Ra-} C (= O) group in which ^Ra is heteroalkyloxy. Representative examples include 1-acetyloxy-methoxycarbonyl (Me-C (= O) -OCH ₂ -OC (= O)-) and the like.

A "heteroaryl" is a 1, 2 or 3 ring hetero selected from the group consisting of N, O or S, with the understanding that the bonding point of the heteroaryl radical is on the aromatic ring. It means a monovalent monocyclic or bicyclic radical consisting of 5 to 12 ring atoms having at least one aromatic ring containing an atom, and the remaining ring atom is C. The heteroaryl ring is independent of one or more substituents, preferably one or two substituents, selected from the group consisting of alkyl, haloalkyl, heteroalkyl, hydroxy, alkoxy, halo, nitro or cyano. It may be replaced. More specifically, the term heteroaryl includes, but is not limited to, pyridyl, furanyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, isooxazolyl, pyrrolyl, pyrazolyl, pyrimidinyl, benzofuranyl, tetrahydrobenzofuranyl, isobenzofuranyl. , Benzothiazolyl, benzoisothiazolyl, benzotriazolyl, indrill, isoindrill, benzoxazolyl, quinolyl, tetrahydroquinolinyl, isoquinolyl, benzoimidazolyl, benzoisooxazolyl or benzothienyl, imidazole [1,2-a] -Pyridinyl, imidazole [2,1-b] thiazolyl and derivatives thereof are included.

"Heteroaralkyl" is ^{a -R a} R ^{b radical in which Ra} is an alkylene group and R ^b is a heteroaryl group, such as pyridine-3-ylmethyl, imidazolylethyl, pyridinylethyl, 3- (benzofuran-2-yl). It means propyl and so on.

"Heteroalkyl-substituted cycloalkyl" means a cycloalkyl radical as defined herein, with the understanding that the heteroalkyl radical is attached to the cycloalkyl radical via a carbon-carbon bond. One, two or three hydrogen atoms in the cycloalkyl radical have been replaced with heteroalkyl groups. Representative examples include, but are not limited to, 1-hydroxymethylcyclopentyl, 2-hydroxymethylcyclohexyl and the like.

"Heterosubstituted cycloalkyl" means the cycloalkyl radical as defined herein, where one, two or three hydrogen atoms in the cycloalkyl radical are hydroxy, alkoxy, amino, acylamino, mono. Alkoxyamino, dialkylamino, oxo (C = O), imino, hydroxyimino (= NOH), NR'SO ₂ R ^d (in the formula, R'is hydrogen or alkyl, and R ^d is alkyl, cycloalkyl. , Hydroxyalkyl, amino, monoalkylamino or dialkylamino), -XY-C (O) R (in the formula, X is O or NR', Y is alkylene or present Instead, R is hydrogen, alkyl, haloalkyl, alkoxy, amino, monoalkylamino, dialkylamino or optionally substituted phenyl, and R'is H or alkyl), or -S (O). _n R (in the formula, n is an integer of 0-2, thus where n is 0, R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl or thienyl. If n is 1 or 2, R is from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, thienyl, amino, acylamino, monoalkylamino or dialkylamino). It has been replaced by an independently selected substituent. Representative examples include, but are not limited to, 2-, 3- or 4-hydroxycyclohexyl, 2-, 3- or 4-aminocyclohexyl, 2-, 3- or 4-methanesulfonamide-cyclohexyl, and the like. Includes 4-hydroxycyclohexyl, 2-aminocyclohexyl or 4-methanesulfonamide-cyclohexyl.

“Hetero-substituted cycloalkyl-alkyl” ^{means Ra} R ^b −, ^{where Ra} is a hetero-substituted cycloalkyl radical and R ^b is an alkylene radical.

"Heterocycloamino" means a monovalent saturated cyclic group consisting of 4 to 8 ring atoms, one of the ring atoms being N and the remaining ring atoms being C. Representative examples include piperidine and pyrrolidine.

"Heterocyclyl" means a saturated or unsaturated non-aromatic cyclic radical consisting of 3 to 8 ring atoms, where one or two ring atoms are N, O or S (O) _n (formula). Among them, n is a heteroatom selected from 0 to 2), the remaining ring atom is C, and one or two C atoms are optionally replaced by a carbonyl group. You may be. Heterocyclyl rings are alkyl, haloalkyl, heteroalkyl, halo, nitro, cyano, cyanoalkyl, hydroxy, alkoxy, amino, monoalkylamino, dialkylamino, aralkyl,-(X) _n- C (O) R (in the formula, X is O or NR', n is 0 or 1, R is hydrogen, alkyl, haloalkyl, hydroxy (if n is 0), alkoxy, amino, monoalkylamino, dialkylamino or substitutions. May be phenyl, where R'is H or alkyl), -alkylene-C (O) ^Ra (in the formula, ^Ra is alkyl, OR or NR'R', where R is. , Hydrogen, alkyl or haloalkyl, where R'and R "are independently hydrogen or alkyl) or -S (O) _n R (in the formula, n is an integer of 0-2, thus When n is 0, R is hydrogen, alkyl, cycloalkyl or cycloalkylalkyl, and when n is 1 or 2, R is alkyl, cycloalkyl, cycloalkylalkyl, amino, acylamino, monoalkyl. It may be independently substituted with one, two or three substituents selected from the group consisting of amino, dialkylamino or heteroalkyl). More specifically, the term heterocyclyl includes, but is not limited to, tetrahydropyranyl, piperidino, N-methylpiperidin-3-yl, piperazino, N-methylpyrrolidin-3-yl, 3-pyrrolidino, morpholino, thiomorpholino. , Thiomorpholino-1-oxide, thiomorpholino-1,1-dioxide, 4- (1,1-dioxo-tetrahydro-2H-thiopyranyl), pyrrolinyl, imidazolinyl, N-methanesulfonyl-piperidine-4-yl and theirs. Includes derivatives.

A "heterocyclylalkyl" is one in which ^Ra is an alkylene group and ^Rb is a heterocyclyl group as defined above-R ^{a Rb} radical, such as tetrahydropyran-2-ylmethyl, 2- or 3-pi. It means peridinylmethyl, 3- (4-methyl-piperazine-1-yl) propyl and the like.

"(Heterocyclyl) (cycloalkyl) alkyl" means an alkyl radical in which two hydrogen atoms are replaced by a heterocyclyl group and a cycloalkyl group.

"(Heterocyclyl) (heteroaryl) alkyl" means an alkyl radical in which two hydrogen atoms are replaced by a heterocyclyl group and a heteroaryl group.

"Amino" means a -NH ₂ radical.

"Monoalkylamino" means that R is an alkyl, hydroxyalkyl, cycloalkyl or cycloalkylalkyl group as defined above-NHR radicals such as methylamino, (1-methylethyl) amino, hydroxymethylamino. , Cyclohexylamino, Cyclohexylmethylamino, Cyclohexylethylamino, etc.

"Dialkylamino" means a -NRR'radical in which R and R'independently represent an alkyl, hydroxyalkyl, cycloalkyl or cycloalkylalkyl group as defined herein. Representative examples include, but are not limited to, dimethylamino, methylethylamino, di (1-methylethyl) amino, (methyl) (hydroxymethyl) amino, (cyclohexyl) (methyl) amino, (cyclohexyl) (ethyl). Includes amino, (cyclohexyl) (propyl) amino, (cyclohexylmethyl) (methyl) amino, (cyclohexylmethyl) (ethyl) amino and the like.

The "optionally substituted phenyl" is alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, heteroalkyl, halo, nitro, cyano, amino, methylenedioxy, ethylenedioxy and acyl, preferably halo, most preferably halo. A phenyl ring selected from the group consisting of fluoro, which may be independently substituted with one or more substituents, preferably one, two or three substituents, more preferably two substituents. means.

Therefore, in a preferred embodiment, the p38 inhibitors for use in the combination drug according to the invention are pamapimod, akumapimod, rosmapimod, dilmapimod, semapimod, AZD7624, ARRY-371797, LY22282820, R9111, PH-797804, BIRB7796, VX-. It is selected from the group consisting of 702, VX-745, SB239063, SB202190, SCIO469 and BMS582949, and their pharmaceutically acceptable salts. More preferred are selected from the group consisting of pamapimod, rosmapimod, LY22282820, BMS582949 or pharmaceutically acceptable salts and mixtures thereof, or pamapimod, rosmapimod, LY2228820, BMS582949 or those pharmaceutically acceptable. Selected from the group consisting of salts, or selected from the group consisting of pamapimod, rosmapimod, dilmapimod, R9111, LY2228820, BMS582949 or those pharmaceutically acceptable salts, or pamapimod, rosmapimod, dilmapimod and R9111 or Those pharmaceutically acceptable salts, more preferably pamapimod, rosmapimod or dilmapimod or those pharmaceutically acceptable salts, even more preferably pamapimod or dilmapimod or their pharmaceutically acceptable salts, especially pamapimod or A p38 inhibitor for use in a combination drug according to the invention, selected from the group consisting of pharmaceutically acceptable salts thereof.

を有するパマピモド、または薬学的に許容されるその塩である。 In a particularly preferred embodiment, the p38 inhibitor has the chemical name 6- (2,4-difluorophenoxy) -2- [3-hydroxy-1- (2-hydroxyethyl) -propylamino] -8-methyl-8H-. Pyrido [2,3-d] pyrimidine-7-one and formula III

Pamapimod, or a pharmaceutically acceptable salt thereof.

Pamapimod and its synthesis are described, for example, in WO2008 / 151992, and WO2002 / 064594, and, for example, Hill RJ, Dabbagh K, Chippard D, Li C, Protein RT, Welch M, Paper E, Song KW, Chang KW, Chang K. Y-N, Roberts RT, Zabka TS, Aud D, Dal Porto J, Manning AM, Peng SL, Goldstein DM, and Wong BR; Pamapimod, a Novel p38 Mitogen-Activated Protein Kinase Inhibitor: Preclinical Analysis of Efficacy and Selectivity J Pharmacol Exp Ther. December 2008, Vol. 327: pp. 610-619.

を有するロスマピモド、または薬学的に許容されるその塩である。 Furthermore, a particularly preferred p38 inhibitor is chemical name 6- (5-((cyclopropylamino) carbonyl) -3-fluoro-2-methylphenyl) -N- (2,2-dimethylpropyl) -3-pyridinecarboxamide. And chemical formula IV

Rosmapimod, or a pharmaceutically acceptable salt thereof.

Rosmapimod is, for example, Cheryyan J, Webb AJ, Sarov-Blat L, Elkhawad M, Wallace SM, Maki-Petaja KM, Collier DJ, Morgan J, Fang Z, WilletTech RN, Willette RN, Willette RN. .. Inhibition of p38 mitogen-activated protein kinase kinase nitric oxide-mediated vasodilation and reduces inflammation in hypercholesterolemia. Circulation, February 8, 2011; Vol. 123 (No. 5): pp. 515-23.

を有するＬＹ２２２８８２０、または薬学的に許容されるその塩である。 Furthermore, even more particularly preferred p38 inhibitors are chemical names 3- (2,2-dimethylpropyl) -5- [4- (4-fluorophenyl) -2- (2-methyl-2-propanil) -1H-imidazole. -5-yl] -3H-imidazole [4,5-b] pyridin-2-amine and chemical formula V

LY2228820, or a pharmaceutically acceptable salt thereof.

LY2228820 is, for example, Campbell RM, Anderson BD, Brooks NA, Brooks HB, Chan EM, De Dios A, Gilmour R, Graff JR, Jambrina E, Mader M, McCann D. , Stancato LF, Starling JJ, Tate C, Velasco JA, Wang Y, Ye XS. Charaction of LY2228820 dimesislate, a potent and selective inhibitor of p38 MAPK with inhibitor activity. Mol Cancer The. February 2014; Volume 13 (No. 2): pp. 364-74.

を有するＢＭＳ５８２９４９、または薬学的に許容されるその塩である。 Furthermore, even more particularly preferred p38 inhibitors are chemical names 4- (5- (cyclopropylcarbamoyl) -2-methylphenylamino) -5-methyl-N-propylpyrrolo [1,2-f] [1,2, 4] Triazine-6-carboxamide and chemical formula VI

BMS582949, or a pharmaceutically acceptable salt thereof.

BMS582949 is, for example, Liu C, Lin J, Wobbleski ST, Lin S, Hynes J, Wu H, DJ Man AJ, Li T, Wityak J, Gilloly KM, Pitt S, Shen DR, Zhang RF, McIn L, Shuster DJ, Zhang H, Marathe PH, Doweyko AM, Sack JS, Kilowatt SE, Kish KF, Newitt JA, McKinnon M, Dodd JH, Barrish JC, Schieven. Disease of 4- (5- (cyclopolycarbamoyl) -2-methylphenylamino) -5-methyl-N-propylpyrrolo [1,2-f] [1,2,4] triazine-6-carboxamide (BMS-58) p38-alpha MAP kinase inhibitor for the treatment of inflammation diseases. J Med Chem. September 23, 2010; Volume 53 (No. 18): pp. 6629-39.

によって表される。 Akumapimod has the chemical name 3- [5-amino-4- (3-cyanobenzoyl) -1H-pyrazole-1-yl] -N-cyclopropyl-4-methylbenzamide, eg, De Buck S, Heeber. W, Nitrile A, Straube F, Emotte C, Bruin G, Womensner R. et al. Population PK-PD Model for Tolerance Assessment to the p38 MAP Kinase Tolerance BCT197. CPT Pharmacometrics Sys Sys Pharmacol. December 2015; Volume 4 (No. 12): Structural formulas described on pages 691-700 and shown below:

Represented by.

によって表される。 Dilmapimod is, for example, Christie JD, Vasleph S, Chang PK, May AK, Gunn SR, Yang S, Hardee's K, Kahl L, Powerey WM, Lipson DA, Bayliff AI, Lazaar. A Randomized Dose-Escalation Study of the Safety and Anti-Inflammatory Activity of the p38 Mitogen-Activated Protein Kinase Inhibitor Dilmapimod in Severe Trauma Subjects at Risk for Acute Respiratory Distress Syndrome. Crit Care Med. September 2015; Volume 43 (No. 9): Structural formulas described on pages 1859-69 and shown below:

Represented by.

によって表される。 Semapimod is described, for example, by Bianchi, M. et al. Ulrich, P.M. Bloom, O.D. Meistrell m, M. et al. , I. I. Zimmermann, G.M. A. Schmidtmayerova, H. et al. Bukrinsky, M.D. Donnelley, T. et al. Bucala, R. et al. Cherry, B.I. Manogue, K. et al. R. Totorani, A. et al. J. Cerami, A. et al. Tracey, K. et al. J. (March 1995). Molecular Medicine (Cambridge, Mass.). Volume 1 (No. 3): pp. 254-266, or, for example, Wang J, Grishin AV, Ford HR. Experimental Anti-Inflammatory Drug Semapimod Inflammation TLR Signaling by Targeting the TLR Chaperone gp 96. J Immunol. June 15, 2016; Volume 196 (No. 12): Structural formulas described on pages 5130-7 and shown below:

Represented by.

によって表される。 AZD7624 is described, for example, by Patell N, Cunoosamy D, Hegelund-Myrback T, Pehrson R, Taib Z, Jansson P, Lundin S, Greenaway S, Greenaway G, Greenaway L. et al. AZD7624, an inhaled p38 inhibitor for COPD, attendates lung and systemic inflammation after LPS Challenge in humans. Euro Resp J. DOI: 10.1183 / 13993003.1, described in September 2015, structural formula:

Represented by.

によって表される。 ARRY-371797 can be described, for example, by Muchir A, Wu W, Choi JC, Iwata S, Morrow J, Homma S, Woman HJ. Abnormal p38-alpha mitogen-activated protein kinase sensing in dilated cardiomyopathy caused by lamin A / C gene mutation. Hum Mol Genet. October 1, 2012; Volume 21 (No. 19): pp. 4325-33, structural formula shown below:

Represented by.

によって表される。 R9111 and its synthesis are described in WO2005 / 047284 and, for example, Hill RJ, Dabbagh K, Chippard D, Li C, Suttmann RT, Welch M, Papp E, Song KW, Chang KC, Leafer D, Kim-R. Zabka TS, Aud D, Dal Porto J, Manning AM, Peng SL, Goldstein DM, and Wong BR; Pamapimod, a Novel p38 Mitogen-Activated Protein Kinase Inhibitor: Preclinical Analysis of Efficacy and Selectivity J Pharmacol Exp Ther. December 2008, Vol. 327: pp. 610-619, structural formula:

Represented by.

によって表される。 PH-779804 is, for example, Xing L, Devadas B, Devraj RV, Serness SR, Shieh H, Walker JK, Mao M, Messaging D, Samas B, Yang JZ, Anderson GD, Webb EG. Discovery and charaction of atropisomer PH-779804, a p38 MAP kinase inhibitor, as a clinical drug candidate. ChemmedChem. February 6, 2012; Volume 7 (No. 2): pp. 273-80, structural formula shown below:

Represented by.

によって表される。 BIRB796 is described, for example, by Dietrich J, Hulme C, Hurley LH. The design, synthesis, and evolution of 8 hybrid DFG-out allosteric kinase inhibitors: a structural analysis of the binding Bioorg Med Chem. August 1, 2010; Volume 18 (No. 15): pp. 5738-48, structural formula shown below:

Represented by.

によって表される。 VX-702 can be described, for example, by Damjanov N, Kaufman RS, Speaker-Green GT. Efficacy, pharmacodynamics, and safety of VX-702, a novel p38 MAPK inhibitor, in reheumatoid arthritis: results of two randomized, led to Arthritis Rheum. May 2009; Volume 60 (No. 5): Described on pages 1232-41 and the structural formula shown below:

Represented by.

によって表される。 VX-745 is, for example, Duffy JP, Harrington EM, Salituro FG, Cochran JE, Green J, Gao H, Bemis GW, Evindar G, Gallulo VP, Ford PJ, Germann UA, Germann UA, P, Jones P, Hung C, Pazhanismy S, Wang YM, Murkko MA, Su MS. The Discovery of VX-745: A Novel and Selective p38-alpha Kinase Inhibitor. ACS Med Chem Let. July 28, 2011; Volume 2 (No. 10): pp. 758-63, structural formula shown below:

Represented by.

によって表される。 SB239603 can be described, for example, by Strassburger M, Braun H, Reymann KG. Anti-inflammatory treatment with the p38 mitogen-activated protein kinase inhibitor SB239063 is neuroprotective, decreases the number of activated microglia and facilitates neurogenesis in oxygen-glucose-deprived hippocampal slice cultures. Eur J Pharmacol. September 11, 2008; Volume 592 (No. 1-3): Structural formulas described on pages 55-61 and shown below:

Represented by.

によって表される。 SB202190 is, for example, Hirosawa M, Nakahara M, Otosaka R, Imoto A, Okazaki T, Takahashi S. et al. The p38 patway inhibitor SB202190 activates MEK / MAPK to stimulate the growth of leukemia cells. Leuk Res. May 2009; Volume 33 (No. 5): Structural formulas described on pages 693-9 and shown below:

Represented by.

によって表される。 SCIO469 includes, for example, Sokol L, Cripe L, Kantarjian H, Seekeres MA, Palmar S, Greenberg P, Goldberg SL, Bhushan V, Shammo J, Hohl R, Verma A, GiLa, and Gar. J, List AF. Randomized, dose-escalation study of the p38-alpha MAPK inhibitor SCIO-469 in patients with myelodysplastic syndrome. Leukemia. April 2013; Vol. 27 (No. 4): pp. 977-80, structural formula shown below:

Represented by.

Combination Medicine As outlined above, in the first aspect, the invention is used in a method of preventing or treating a fibrotic disease or disorder in a subject, the following:
Provided are a combination drug comprising (a) a PPAR agonist (b) a p38 kinase inhibitor and optionally (c) one or more pharmaceutically acceptable diluents, additives or carriers.

Useful PPAR agonists are as defined above. In one embodiment, the PPAR agonist activates PPAR gamma and / or PPAR alpha. In a preferred embodiment, the PPAR agonist is selected from the group consisting of pioglitazone, rosiglitazone, troglitazone, phenofibrate, bezafibrate and pharmaceutically acceptable salts thereof. In a more preferred embodiment, the PPAR agonist is a PPAR gamma agonist, preferably consisting of pioglitazone, rosiglitazone and troglitazone or pharmaceutically acceptable salts thereof, in particular pioglitazone or a pharmaceutically acceptable salt thereof. A PPAR gamma agonist selected from the group. In a particularly preferred embodiment, the PPAR agonist is pioglitazone hydrochloride.

Useful p38 kinase inhibitors are as defined above. In a preferred embodiment, the p38 kinase inhibitor inhibits p38-alpha, p38-beta, p38-gamma or p38-delta, or a combination thereof, preferably p38-alpha and / or p38-beta. , More preferably it inhibits p38-alpha. Further useful p38 kinase inhibitors are compounds of formula I or II as defined above, or pharmaceutically acceptable salts thereof. More useful p38 kinase inhibitors are pamapimod, akumapimod, rosmapimod, dilmapimod, semapimod, AZD7624, ARRY-371797, LY2228820, R9111, PH-779804, BIRB796, VX-702, VX-745, SB239063S. And their pharmaceutically acceptable salts, in particular selected from the group consisting of pamapimod, rosmapimod, LY22282820, BMS582949 or their pharmaceutically acceptable salts and mixtures, or pamapimod, akumapimod, rosmapimod, dilmapimod, semapimod. , AZD7624, ARRY-371797, LY2228820, R9111, PH-779804, BIRB796, VX-702, VX-745, SB239063, SB202190, SCIO469, BMS582949 and their pharmaceutically acceptable salts, in particular Pamapimod, Rosmapimod, L. , BMS582949 or their pharmaceutically acceptable salts, preferably pamapimod, rosmapimod, dilmapimod or R9111, or their pharmaceutically acceptable salts, more preferably pamapimod or dilmapimod, or those pharmaceutically acceptable. A p38 kinase inhibitor selected from the group consisting of salts, more specifically pamapimod or a pharmaceutically acceptable salt thereof.

The combinational medicament according to the present invention is, for example, a preparation combination or a pharmaceutical composition for simultaneous use, individual use or sequential use.

The term "preparation combination", as used herein, refers to a variety of constants of the PPAR agonist and the p38 inhibitor, including in individual forms, eg, as individual tablets, or in distinct amounts of the active ingredient. In particular, it is defined as the "kit of parts" in the sense that it can be administered independently, either by the use of a combination of. The ratio of the amount of PPAR agonist to the amount of p38 inhibitor that will be administered in the preparation combination will vary, for example, to address the need for a subpopulation of patients to be treated, or the need for a single patient. Obtain, these needs may vary depending on the patient's age, gender, weight, and the like. The individual parts of the preparation combination (kit of parts) can be administered simultaneously or sequentially with respect to any part of the kit of parts, i.e. in chronological order, eg, at various time points, and at equal or different time intervals. Can be shifted with.

The term "pharmaceutical composition" refers to a fixed-dose combination (FDC) comprising a PPAR agonist and a p38 inhibitor combined in a single dosage form with a given combination of individual doses. Point to.

The combination drug may also be used as an add-on therapy. As used herein, "add-on" or "add-on therapy" means an assemblage of reagents for use in treatment, and the subject to be treated is in addition to the first treatment regimen. Before starting a second treatment regimen consisting of one or more different reagents, a first treatment regimen consisting of one or more reagents was started, and as a result, the reagents used in this treatment. Not all start at the same time. For example, adding treatment with a p38 inhibitor to a patient who has already received PPAR agonist therapy and vice versa.

In a preferred embodiment, the combination drug according to the invention is a preparation combination.

In a more preferred embodiment, the combination drug according to the invention is a pharmaceutical composition, i.e. a constant dose combination.

The amount of PPAR agonist and p38 inhibitor administered includes, for example, the particular PPAR agonist administered, the route of administration, the condition to be treated, the target area to be treated, and the subject or host to be treated. It will vary according to the particular circumstances surrounding it, depending on factors such as the particular compound, disease state and its severity.

In one embodiment, the present invention provides a combination drug comprising a PPAR agonist and a p38 inhibitor, wherein the PPAR agonist and the p38 inhibitor are present in therapeutically effective amounts.

In a preferred embodiment, the invention is a combination drug comprising a PPAR agonist and a p38 inhibitor, wherein the PPAR agonist and the p38 inhibitor produce an additive therapeutic effect, i.e. the PPAR agonist and the p38 inhibitor. However, there is provided a combination drug that is present in an amount that produces an additive therapeutic effect.

As used herein, the term "additive" is derived from the fact that the effects achieved using the combination drugs of the invention use these agents, namely PPAR agonists and p38 inhibitors, as monotherapy. It means that it is almost the total of the actions that occur. Advantageously, the additive effect may achieve higher efficacy at the same dose and a longer duration of response to treatment.

In a more preferred embodiment, the invention is a combination drug comprising a PPAR agonist and a p38 inhibitor, wherein the PPAR agonist and the p38 inhibitor produce a synergistic therapeutic effect, i.e. the PPAR agonist and the p38 inhibitor. However, there is provided a combination drug that is present in an amount that produces a synergistic therapeutic effect.

In an even more preferred embodiment, the invention is a combination drug comprising a PPAR agonist and a p38 inhibitor, wherein the PPAR agonist and the p38 inhibitor are interleukin / interleukin receptors and / or TNF / TNF receptors. The PPAR agonist and the p38 inhibitor produce a synergistic therapeutic effect on the regulation of the expression of the gene and / or the CC and CC motif chemokine gene families, more particularly the PPAR agonist and the p38 inhibitor. Regarding the regulation of expression of one or more interleukin / interleukin receptor genes selected from the group consisting of 11, interleukin 12B and interleukin 18 receptor 1, and / or TNF receptor superfamily member 11b, TNF. Regarding the regulation of expression of the TNF / TNF receptor gene selected from the group consisting of superfamily member 9, TNF receptor superfamily member 10b and TNF superfamily member 18, and / or CC motif chemokine ligand 7, C- C motif chemokine ligand 4, CC motif chemokine ligand 3, CC motif chemokine ligand 12, CC motif chemokine ligand 2, CC motif chemokine ligand 8, CC motif chemokine ligand 24, CX- Synergistic with respect to regulation of expression of C-C and C-X-C motif chemokine genes selected from the group consisting of C-motif chemokine ligand 10, C-X-C motif chemokine ligand 5, and C-X-C motif chemokine ligand 3. One or more of the PPAR agonist and the p38 inhibitor selected from the group consisting of interleukin 6, interleukin 11, interleukin 12B and interleukin 18 receptor 1, which produce a therapeutic effect. Regarding the regulation of interleukin / interleukin receptor gene expression and / or selected from the group consisting of TNF receptor superfamily member 11b, TNF superfamily member 9, TNF receptor superfamily member 10b and TNF superfamily member 18. Provided are a combination drug that produces a synergistic therapeutic effect on the regulation of the expression of the TNF / TNF receptor gene.

As used herein, the term "synergistic" results from the use of these agents, namely PPAR agonists and p38 inhibitors, as monotherapy for the effects achieved using the combination drugs of the invention. It means that it is larger than the total action. Advantageously, such synergies can achieve higher efficacy at the same dose and longer duration of response to treatment.

In one embodiment, the invention is a combination drug comprising a p38 inhibitor and a PPAR agonist, wherein the amount of the PPAR agonist in the combination is about 0.1 to about 45 mg, about 0.1 to about 30 mg. Alternatively, a combination drug, which is about 0.1 to about 15 mg, is provided. When the PPAR agonist is in the form of a pharmaceutically acceptable salt, the amount of PPAR agonist provided herein is calculated based on the individual free base.

In a preferred embodiment, the invention is a combination drug comprising a p38 inhibitor and pioglitazone or a pharmaceutically acceptable salt thereof, wherein the amount of pioglitazone or pharmaceutically acceptable salt thereof in the combination is Pioglitazone, or a pharmaceutically acceptable salt thereof, is used to provide a combination drug that is usually less than the dose required for the treatment of diabetes.

In one embodiment, the invention is a combination drug comprising a p38 inhibitor and a PPAR agonist, wherein the amount of the p38 inhibitor in the combination is about 1 to about 500 mg, or about 1 to about 450 mg, or About 1 to about 400 mg, or about 1 to about 350 mg, or about 1 to about 300 mg, or about 1 to about 250 mg, or about 1 to about 200 mg, or about 1 to about 150 mg, or about 1 to about 125 mg, or about Combinations of 1 to about 100 mg, or about 10 to about 125 mg, or about 10 to about 100 mg, or about 20 to about 100 mg, or about 30 to about 100 mg, or about 40 to about 100 mg, or about 50 to about 100 mg. Provide medicine.

In a preferred embodiment, the combination drug of the invention is a pharmaceutical composition (ie, the constant dose combination outlined above). In one embodiment, the combination pharmaceuticals of the invention are pharmaceutical compositions and other medical or pharmaceutical agents, such as one or more pharmaceutically acceptable diluents, additives or Includes carrier.

Dosage and Treatment The terms "treatment" / "treatment", as used herein, may be: (1) suffering from, or susceptible to, a situation, disorder or condition. The appearance of clinical manifestations of conditions, disorders or conditions that have developed in animals, especially mammals, especially humans, who have not yet experienced this situation, disorder or condition, or who do not exhibit these clinical or subclinical symptoms. Delaying; (2) inhibiting a situation, disorder or condition (eg, in the case of maintenance treatment, suppressing the progression or recurrence of the disease, the progression or recurrence of at least one clinical sign or its subclinical symptoms, Reducing or delaying); and / or (3) Relieving the condition (ie, causing at least one relapse of the condition, disorder or condition, or its clinical or subclinical symptoms). The benefit to the patient being treated is either statistically significant or at least perceived by the patient or physician. However, it will be appreciated that the outcome may not always be an effective treatment when the drug is administered to the patient to treat the disease.

Prophylactic measures include prophylactic measures. For prophylactic application, the combination drugs of the invention are administered to a subject suspected of having or at risk of developing fibrotic diseases or disorders. For therapeutic use, the combination drug of the present invention is administered to a subject, such as a patient already suffering from a fibrotic disease or disorder, in an amount sufficient to cure, or at least partially suppress, the symptoms of the disease. NS. The effective amount for this use will depend on the severity and course of the disease, previous treatment, the subject's health and response to the drug, and the judgment of the treating physician. In order to improve the symptoms of the subject's disease or condition if the subject's condition has not improved, or to control or limit it otherwise, the combination drug of the invention is long-term, i.e., the subject's lifetime. It may be administered for a long period of time, including the entire period of.

If the condition of the subject is not improved, the combination drug of the present invention may be administered continuously. Alternatively, the dose of drug administered may be temporarily reduced or suspended for a period of time (ie, a "drug holiday").

The combination drug according to the invention is preferably administered orally, topically, injected, eye, topically (eg, subconjunctival, intravitreal, post-ocular or anterior chamber), systemic (ie, enteral or parenteral). Suitable for administration by inhalation, that is, the combination is administered locally to the lungs. More preferably, the combination drug according to the invention is suitable for oral, topical, injectable and / or inhaled administration, and most preferably for oral administration to a subject, a therapeutically effective amount of the active ingredient. And optionally include one or more suitable pharmaceutically acceptable diluents, additives or carriers.

Unless otherwise indicated, the combination drug according to the present invention is prepared by a method known per se, for example, by a conventional mixing method, granulation method, coating method, dissolution method or lyophilization method. Any of the usual pharmaceutical media, such as carriers, diluents, granulators, lubricants, binders, disintegrants, etc., may be used to prepare the combinations for oral dosage forms. Tablets and capsules are the most advantageous oral dosage unit forms due to their ease of administration, in which case it is clear that solid pharmaceutical carriers are used.

In a preferred embodiment, the combination drug according to the invention is a combination for oral administration. As shown above, the combination drug for oral administration is preferably a pharmaceutical composition, i.e. a fixed dose combination.

In one embodiment, the combination drug according to the invention is a combination for topical administration. As shown above, the combination drug for topical administration is preferably a pharmaceutical composition, i.e. a fixed dose combination.

In another preferred embodiment, the combination drug according to the invention is a combination for injection administration. As shown above, the combination drug for injection administration is preferably a pharmaceutical composition, i.e. a fixed dose combination.

In one embodiment, the combination drug according to the invention is a combination for topical administration of the eye. As shown above, the combination drug for topical administration of the eye is preferably a pharmaceutical composition, i.e. a fixed dose combination.

In another preferred embodiment, the combination drug according to the invention is a combination for systemic, i.e., enteric or parenteral administration. As shown above, the combination drug for systemic administration is preferably a pharmaceutical composition, i.e. a fixed dose combination.

In another preferred embodiment, the combination drug according to the invention is a combination for administration by inhalation, eg, as an intranasal spray or dry powder or an aerosol inhaler. For delivery by inhalation, the active compound is preferably in the form of fine particles. They can be prepared by a variety of techniques, including spray drying, lyophilization and micronization. Aerosol generation is performed using, for example, a pressure-propelled jet atomizer or ultrasonic atomizer, preferably a propellant-propelled metered aerosol, or, for example, a micronizing active compound from an inhalation capsule or other "dry powder" delivery system. It can be carried out using the propellant-free administration of. Microparticles for delivery by inhalation can be formulated with additives that aid delivery and release. For example, in a dry powder formulation, the microparticles may be formulated with large carrier particles that assist in the flow from the DPI to the lungs. Suitable carrier particles are known and include lactose particles. Lactose particles can have an aerodynamic central particle size larger than 90 μm.

The active compound may be administered as described depending on the inhaler system used. In addition to the active compound, the dosage forms are, for example, propellants (eg, Frigen in the case of metered aerosols), surfactants, emulsifiers, stabilizers, preservatives, flavoring agents, fillers (eg, in the case of powdered inhalants). , Lactose), or, where appropriate, additional additives such as additional active compounds may be added.

For inhalation, a number of systems are available in which an aerosol of optimal particle size can be generated and administered using the inhalation technique appropriate for the patient. Adapters (spacers, expanders) and pear-shaped containers (eg, Nebulator®, Volumatic®), and automatic spray discharge devices (especially for powder inhalers) for metered aerosols (especially for powder inhalers). In addition to the use of emtiting a puffer spray (Autohaler®), several technical solutions are available (eg, Dischaler®, Rotadsky®, Turbohaler®, Or, for example, the inhaler described in EP-A-055321). In addition, the combinations of the invention may be delivered in a multi-chamber device, thus allowing the separate storage and administration of PPAR agonists and p38 inhibitors according to the invention.

In a more preferred embodiment, the combination drug according to the invention is administered to the subject orally, topically, by injection, or even more preferably orally.

In a preferred embodiment, the fibrotic disease or disorder is pulmonary fibrosis and the combination drug according to the invention is a combination for oral administration, i.e. orally administered. As shown above, the combination drug for oral administration is preferably a pharmaceutical composition, i.e. a fixed dose combination.

In a more preferred embodiment, the fibrotic disease or disorder is pulmonary fibrosis and the combination drug according to the invention is a combination for administration by inhalation, i.e. administered to the lungs. As shown above, the combination drug for administration by inhalation is preferably a pharmaceutical composition, i.e. a constant dose combination.

In one embodiment, the fibrotic disease or disorder is liver fibrosis and the combination drug according to the invention is a combination for oral administration, i.e. orally administered. As shown above, the combination drug for oral administration is preferably a pharmaceutical composition, i.e. a fixed dose combination.

In one embodiment, the fibrotic disease or disorder is nephrogenic fibrosis and the combination drug according to the invention is a combination for oral administration, i.e. orally administered. As shown above, the combination drug for oral administration is preferably a pharmaceutical composition, i.e. a fixed dose combination.

In one embodiment, the fibrotic disease or disorder is ocular fibrosis and the combination drug according to the invention is a combination for oral, injectable or topical administration, i.e. orally, by injection or topically. Will be done. As shown above, the combination drug for oral, injectable or topical administration is preferably a pharmaceutical composition, i.e. a fixed dose combination.

In one embodiment, the fibrotic disease or disorder is cutaneous fibrosis and the combination drug according to the invention is a combination for oral or topical administration, i.e. orally or topically administered. As shown above, the combination drug for oral or topical administration is preferably a pharmaceutical composition, i.e. a fixed dose combination.

Combination medications for oral or systemic, ie enteric or parenteral administration are in unit dosage forms such as tablets, capsules or suppositories.

In one embodiment, the invention is a pharmaceutical composition comprising a PPAR agonist such as pioglycazone, a p38 inhibitor such as pamapimod, and at least one pharmaceutically acceptable carrier, a solution for ocular administration. Provided are pharmaceutical compositions, which are agents or suspensions (ie, eye drops), or ointments for the eye.

In one embodiment, the invention is a pharmaceutical composition comprising a PPAR agonist such as pioglitazone, a p38 inhibitor such as pamapimod, and at least one pharmaceutically acceptable carrier, the tablet or capsule. Provided are pharmaceutical compositions, preferably tablets.

Such amounts do not need to constitute a therapeutically effective amount by themselves, as the unit content of the active ingredient in individual doses can be reached by administration of multiple dosage units. The composition according to the invention can contain, for example, a therapeutically effective amount of the active ingredient, which is about 10% to about 100%.

When the combination drug according to the present invention is a preparation combination, the PPAR agonist need not be administered in the same form as the p38 inhibitor. As an example, the PPAR agonist may be administered as a powder by inhalation, while the p38 inhibitor may be orally administered as a tablet and vice versa.

In some embodiments, the combination drug of the invention is administered to a subject at a dose comprising a dose of said PPAR agonist that is less than the dose required to treat diabetes using a PPAR agonist. In some embodiments, the combination drug of the invention is one-third to one-ninth less than the upper limit dose evaluated and tested for the treatment of diabetes, especially for the treatment of diabetes in humans. It is administered to the subject at a dose that includes a dose of PPAR agonist that is one-third to one-ninth less than the upper limit dose evaluated and tested in. The upper limit doses evaluated and tested for the treatment of diabetes in humans typically range from about 15-45 mg / day for PPAR gamma agonists such as pioglitazone hydrochloride. In some embodiments, the PPAR agonist dose used reduces or does not cause the side effects observed in the treatment of diabetes with said PPAR agonist.

In some embodiments, the combination drug of the invention is less than the active dose for anti-diabetic or anti-lipid abnormality associated with the treatment of the PPAR agonist, especially in humans, the anti-diabetic or anti-lipid abnormality of the PPAR agonist. It is administered to the subject at a dose that includes a dose of PPAR agonist that is less than the active dose for action.

A typical dosing regimen of pioglitazone or a pharmaceutically acceptable salt thereof in the treatment of diabetes comprises 15-45 mg of pioglitazone once daily.

In some embodiments, the combination drug of the invention is at a dose selected from the group consisting of peroxisome proliferators, rosiglitazones, troglitazones, peonofibrate, bezafibrates and salts thereof which are pharmaceutically acceptable. PPAR agonists, usually PPAR gamma agonists, PPAR alpha agonists and / or PPAR alpha / gamma dual agonists, preferably PPAR gamma agonists and / or PPAR alpha agonists, more preferably PPAR gamma agonists and / or PPAR alpha agonists, even more preferably. Is a PPAR gamma agonist, even more preferably pioglycazone or a pharmaceutically acceptable salt thereof, most preferably 0.1 to 45 mg / day, preferably 0.1 to 10 mg / day, more preferably about 5 mg / day of pioglycazone. Hydrochloride; and certain doses of p38 inhibitors, such as compounds of formula I or II, in particular compounds of formula I, preferably pamapimod, akumapimod, rosmapimod, dilmapimod, semapimod, AZD7624, ARRY-371797, LY2228820, R9111, PH-779804. , BIRB796, VX-702, VX-745, SB239063, SB202190, SCIO469 and BMS582949 or p38 inhibitors selected from the group consisting of pharmaceutically acceptable salts thereof, more preferably 1 to 500 mg / day, preferably It is orally administered to humans at a dose containing 10 to 250 mg / day, more preferably 25 to 150 mg / day, most preferably about 75 mg / day of peroxisome proliferator or a pharmaceutically acceptable salt thereof.

Dosage regimen The exemplary treatment regimen requires administration once daily, twice daily or three times daily, preferably once daily and / or twice daily. The combinations of the invention are usually administered on multiple occasions. The interval between single doses can be, for example, daily, daily or less than every other day. The combinations of the invention may be administered as a continuous, non-interruptive treatment. The combinations of the invention may also be administered in a regimen in which the subject undergoes a treatment cycle with a discontinuation period due to a drug holiday or non-treatment period. Thus, the combinations of the invention are administered according to the intervals selected above for a continuous period of 1 week or part thereof, 2 weeks, 3 weeks, 4 weeks, 5 weeks or 6 weeks, followed by 1 week or Some of them may be suspended for 2 weeks, 3 weeks, 4 weeks, 5 weeks or 6 weeks. The combination of treatment and non-treatment intervals is called a cycle. This cycle may be repeated once or multiple times. The procedure may be repeated one or more times, and two or more different cycles may be used in combination. Intervals can also be irregular and can be guided either by worsening or ameliorating the patient's condition as indicated by the appearance or remission of symptoms, or by objective evidence of the appearance or remission of the disease. In such cases, treatment may be initiated, interrupted as needed, and resumed only if the symptom or objective measure indicates a recurrence of the disease. In a preferred embodiment, the combination drug according to the invention is administered once daily.

Kits / Products In one aspect, the invention is a kit for use in a method of preventing or treating a fibrotic disease or disorder in a subject, using the combination drug disclosed herein and the kit. A kit is also provided, including instructions for doing so. Preferred PPAR agonists and preferred p38 kinase inhibitors composed of the combination drugs are as described above.

In some embodiments, the kit comprises a carrier, package or container that is segmented to accommodate one or more containers such as vials, tubes, etc., each of which is described herein. Includes one of the individual elements used in the method. Suitable containers include, for example, bottles, vials, syringes and test tubes. In other embodiments, the container is made of various materials, such as glass or plastic.

The articles provided herein will generally include one or more combination drugs and packaging materials disclosed herein. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, and selected compositions and intended dosage regimens and treatments. Any suitable packaging material is included.

Prevention or Treatment of Fibrotic Diseases or Disorders In one aspect, the invention is a combination drug described herein for use in methods of preventing or treating fibrous diseases or disorders in a subject. Less than:
Provided are a combination drug comprising (a) a PPAR agonist (b) a p38 kinase inhibitor and optionally (c) one or more pharmaceutically acceptable diluents, additives or carriers.

Similarly, the use of the combination drugs described herein for producing a drug that prevents or treats a fibrotic disease or disorder in a subject is provided.

Similarly, the use of the combination drugs described herein is provided to prevent or treat a fibrotic disease or disorder in a subject.

Similarly, a method of preventing or treating a fibrotic disease or disorder in a subject is provided that comprises administering to the subject a therapeutically effective amount of a combination drug described herein. ..

In a preferred embodiment, the invention is a combination medicament described herein for use in a method of preventing or treating a fibrotic disease or disorder in a subject, wherein the fibrotic disease or disorder is a lung. Provided are a combination drug selected from the group consisting of fibrosis, liver fibrosis, renal fibrosis, myocardial fibrosis, ocular fibrosis or cutaneous fibrosis.

In a more preferred embodiment, the invention provides the combination drugs described herein for use in methods of preventing or treating pulmonary fibrosis.

In an even more preferred embodiment, the invention is a combination medicament described herein for use in methods of preventing or treating pulmonary fibrosis, wherein pulmonary fibrosis is idiopathic pulmonary fibrosis ( To provide a combination drug selected from the group consisting of IPF), familial interstitial pulmonary fibrosis, nonspecific interstitial pneumonia (NSIP), unexplained organizing pneumonia (COP), sarcoidosis and asbestososis. ..

In an even more preferred embodiment, the invention is a combination medicament described herein for use in methods of preventing or treating pulmonary fibrosis, wherein pulmonary fibrosis is idiopathic pulmonary fibrosis ( IPF), familial interstitial pulmonary fibrosis, nonspecific interstitial pneumonia (NSIP), unexplained organizing pneumonia (COP), sarcoidosis, chronic obstructive pulmonary disease (COPD) and asbestososis Provide a combination drug of choice.

In certain preferred embodiments, the present invention is a combination medicament described herein for use in methods of preventing or treating pulmonary fibrosis, wherein pulmonary fibrosis is idiopathic pulmonary fibrosis ( IPF), a combination drug selected from the group consisting of familial interstitial pulmonary fibrosis and asbestos disease.

In a further specific preferred embodiment, the invention is a combination medicament described herein for use in methods of preventing or treating pulmonary fibrosis, wherein pulmonary fibrosis is idiopathic pulmonary fibrosis. Provided is a combination drug selected from the group consisting of (IPF), familial interstitial pulmonary fibrosis, chronic obstructive pulmonary disease (COPD) and astrocytosis.

In a more specific preferred embodiment, the invention provides the combination drugs described herein for use in methods of preventing or treating idiopathic pulmonary fibrosis (IPF).

In one embodiment, the invention is used in a method of preventing or treating a fibrotic disease or disorder in a subject:
(A) PPAR agonist (b) p38 kinase inhibitor, and optionally (c) a combination drug comprising one or more pharmaceutically acceptable diluents, additives or carriers.
The p38 kinase inhibitor preferably inhibits p38-alpha, p38-beta, p38-gamma or p38-delta, or a combination thereof, more preferably inhibits p38-alpha and / or p38-beta. Provide combination drugs.

In one embodiment, the invention is used in a method of preventing or treating a fibrotic disease or disorder in a subject:
(A) PPAR agonist (b) p38 kinase inhibitor, and optionally (c) a combination drug comprising one or more pharmaceutically acceptable diluents, additives or carriers.
The p38 kinase inhibitors are pamapimod, akumapimod, rosmapimod, dilmapimod, semapimod, AZD7624, ARRY-371797, LY2228820, R9111, PH-779804, BIRB796, VX-702, VX-745, SB239063, SB239063, SB. Provided are combination drugs selected from the group consisting of those pharmaceutically acceptable salts.

In a further embodiment, the invention is used in a method of preventing or treating a fibrotic disease or disorder in a subject:
(A) PPAR agonist (b) a compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof, a p38 kinase inhibitor, and optionally.
(C) Provided is a combination drug according to the invention comprising one or more pharmaceutically acceptable diluents, additives or carriers.

In a further embodiment, the invention is used in a method of preventing or treating a fibrotic disease or disorder in a subject:
(A) PPAR agonist (b) a compound of formula II as defined herein, or a pharmaceutically acceptable salt thereof, a p38 kinase inhibitor, and optionally.
(C) Provided is a combination drug comprising one or more pharmaceutically acceptable diluents, additives or carriers.

In a preferred embodiment, the invention is used in a method of preventing or treating a fibrotic disease or disorder in a subject:
(A) PPAR agonist (b) pamapimod, or a pharmaceutically acceptable salt thereof, a p38 kinase inhibitor, and optionally.
(C) Provided is a combination drug comprising one or more pharmaceutically acceptable diluents, additives or carriers.

In a more preferred embodiment, the invention is used in a method of preventing or treating a fibrotic disease or disorder in a subject:
(A) PPAR agonist (b) a compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof, a p38 kinase inhibitor, and optionally.
(C) A combination drug comprising one or more pharmaceutically acceptable diluents, additives or carriers.
PPAR gamma agonists provide a combination drug selected from the group consisting of pioglitazone, rosiglitazone and troglitazone, or salts thereof which are pharmaceutically acceptable.

In a more preferred embodiment, the invention is used in a method of preventing or treating a fibrotic disease or disorder in a subject:
(D) PPAR agonist (e) pamapimod, or a pharmaceutically acceptable salt thereof, a p38 kinase inhibitor, and optionally.
(F) A combination drug comprising one or more pharmaceutically acceptable diluents, additives or carriers.
PPAR gamma agonists provide a combination drug selected from the group consisting of pioglitazone, rosiglitazone and troglitazone, or salts thereof which are pharmaceutically acceptable.

In a further embodiment, the invention is used in a method of preventing or treating a fibrotic disease or disorder in a subject:
(A) PPAR gamma agonist (b) A compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof, a p38 kinase inhibitor, and optionally.
(C) Provided is a combination drug comprising one or more pharmaceutically acceptable diluents, additives or carriers.

In a further embodiment, the invention is used in a method of preventing or treating a fibrotic disease or disorder in a subject:
(A) PPAR gamma agonist (b) A compound of formula II as defined herein, or a pharmaceutically acceptable salt thereof, a p38 kinase inhibitor, and optionally.
(C) Provided is a combination drug comprising one or more pharmaceutically acceptable diluents, additives or carriers.

In a preferred embodiment, the invention is used in a method of preventing or treating a fibrotic disease or disorder in a subject:
(A) PPAR gamma agonist (b) A compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof, a p38 kinase inhibitor, and optionally.
(C) A combination drug comprising one or more pharmaceutically acceptable diluents, additives or carriers.
The PPAR gamma agonist is selected from the group consisting of pioglitazone, rosiglitazone, troglitazone and INT131, or pharmaceutically acceptable salts thereof, preferably pioglitazone, rosiglitazone and troglitazone, or those pharmaceutically acceptable. Selected from the group consisting of salt
^{X 1} and X ² in the compound of the formula I are O, respectively.
Z in the compound of the formula I is N,
W in the compound of the formula I is NH,
^{Ar 1} in the compound of formula I is aryl and
^{R 1} in the compound of formula I is heteroalkyl and
^{R 3} in the compound of formula I is alkyl,
Provide combination drugs.

In a more preferred embodiment, the invention is used in a method of preventing or treating a fibrotic disease or disorder in a subject:
(A) PPAR gamma agonists (b) pamapimods, R9111, semapimods, or salts thereof, preferably pamapimods or their pharmaceutically acceptable salts, p38 kinase inhibitors, and optionally.
(C) A combination drug comprising one or more pharmaceutically acceptable diluents, additives or carriers.
The PPAR gamma agonist is selected from the group consisting of pioglitazone, troglitazone, bezafibrates and pharmaceutically acceptable salts thereof.
Provide combination drugs.

In a more preferred embodiment, the invention is used in a method of preventing or treating a fibrotic disease or disorder in a subject:
(A) PPAR gamma agonists (b) Pamapimod, rosmapimod, dilmapimod or R9111, or their pharmaceutically acceptable salts, preferably pamapimod or dilmapimod or their pharmaceutically acceptable salts, more preferably pamapimod or pharmaceuticals. A p38 kinase inhibitor, which is an acceptable salt thereof, and optionally,
(C) Provided is a combination drug comprising one or more pharmaceutically acceptable diluents, additives or carriers.

In a more preferred embodiment, the invention is used in a method of preventing or treating a fibrotic disease or disorder in a subject:
(D) PPAR gamma agonists (e) pamapimod, rosmapimod, dilmapimod or R9111, or their pharmaceutically acceptable salts, preferably pamapimod or dilmapimod or their pharmaceutically acceptable salts, more preferably pamapimod or pharmaceuticals. A p38 kinase inhibitor, which is an acceptable salt thereof, and optionally,
(F) A combination drug comprising one or more pharmaceutically acceptable diluents, additives or carriers.
The PPAR gamma agonist is selected from the group consisting of pioglitazone, rosiglitazone and troglitazone, or pharmaceutically acceptable salts thereof.
Provide combination drugs.

In one embodiment, the invention is used in a method of preventing or treating a fibrotic disease or disorder in a subject:
(A) PPAR agonist (b) p38 kinase inhibitor, and optionally (c) a combination drug comprising one or more pharmaceutically acceptable diluents, additives or carriers.
The PPAR agonist activates PPAR alpha, PPAR gamma or PPAR delta, or a combination thereof.
Provide combination drugs.

In one embodiment, the invention is used in a method of preventing or treating a fibrotic disease or disorder in a subject:
(A) PPAR agonist (b) p38 kinase inhibitor, and optionally (c) a combination drug comprising one or more pharmaceutically acceptable diluents, additives or carriers.
The PPAR agonists are pioglitazone, troglitazone, rosiglitazone, bezafibrate, phenofibrate, clofibrate, gemfibrozil, alegritazal, muragritazal, tesaglitazal, lagaglitazal, salogritazal, GFT505, nabegritazal, GW501516 and INT131 or pharmaceuticals. Selected from the group of salt,
Provide combination drugs.

In one embodiment, the invention is used in a method of preventing or treating a fibrotic disease or disorder in a subject:
(A) PPAR agonist (b) p38 kinase inhibitor, and optionally (c) a combination drug comprising one or more pharmaceutically acceptable diluents, additives or carriers.
The PPAR agonist is selected from the group consisting of pioglitazone, troglitazone, bezafibrate, and pharmaceutically acceptable salts thereof.
Provide combination drugs.

In a preferred embodiment, the invention is used in a method of preventing or treating a fibrotic disease or disorder in a subject:
(A) PPAR agonist (b) p38 kinase inhibitor, and optionally (c) a combination drug comprising one or more pharmaceutically acceptable diluents, additives or carriers.
The PPAR agonist is pioglitazone or a pharmaceutically acceptable salt thereof.
Provide combination drugs.

In a preferred embodiment, the invention is used in a method of preventing or treating a fibrotic disease or disorder in a subject:
(A) PPAR agonist (b) p38 kinase inhibitor, and optionally (c) a combination drug comprising one or more pharmaceutically acceptable diluents, additives or carriers.
The PPAR agonist is selected from the group consisting of pioglitazone, rosiglitazone and troglitazone, or pharmaceutically acceptable salts thereof.
Provide combination drugs.

In a more preferred embodiment, the invention is used in a method of preventing or treating a fibrotic disease or disorder in a subject:
(A) A PPAR agonist, which is pioglitazone or a pharmaceutically acceptable salt thereof.
(B) A combination drug comprising a p38 kinase inhibitor and optionally (c) one or more pharmaceutically acceptable diluents, additives or carriers.

In a more preferred embodiment, the invention is used in a method of preventing or treating a fibrotic disease or disorder in a subject:
(A) Pioglitazone hydrochloride, a PPAR agonist,
(B) A combination drug comprising a p38 kinase inhibitor and optionally (c) one or more pharmaceutically acceptable diluents, additives or carriers.

In a particularly preferred embodiment, the invention is used in a method of preventing or treating a fibrotic disease or disorder in a subject:
(A) A PPAR agonist, which is pioglitazone or a pharmaceutically acceptable salt thereof, preferably pioglitazone hydrochloride.
(B) Pamapimod, or a pharmaceutically acceptable salt thereof, a p38 kinase inhibitor, and optionally.
(C) Provided is a combination drug comprising one or more pharmaceutically acceptable diluents, additives or carriers.

In a more particularly preferred embodiment, the invention for use in a method of preventing or treating a fibrotic disease or disorder in a subject is described below.
(A) A PPAR agonist, which is pioglitazone or a pharmaceutically acceptable salt thereof, preferably pioglitazone hydrochloride.
(B) Pamapimod, or a pharmaceutically acceptable salt thereof, a p38 kinase inhibitor, and optionally.
(C) A combination drug comprising one or more pharmaceutically acceptable diluents, additives or carriers.
The fibrotic disease or disorder is idiopathic pulmonary fibrosis (IPF).
Provide combination drugs.

The examples are intended to illustrate the invention without limiting the invention.

Example 1
Combination therapy with pamapimod and pioglitazone protects against bleomycin-induced pulmonary fibrosis. Summary Bleomycin has been widely used to induce pulmonary fibrosis in mice to study potential therapies. The efficacy of pioglitazone and pamapimod administered individually and in combination compared to the approved drug pirfenidone was tested in a 21-day model of bleomycin-induced pulmonary fibrosis in mice. Once-daily pioglitazone and once-daily pamapimod administered individually and in combination significantly reduced post-normalized lung weight and fibrosis scores compared to vehicle-treated controls. The combination of pamapimod / pioglitazone has been shown to significantly reduce these disease parameters compared to the single-agent group. All treatment groups showed higher efficacy than the positive control group who took pirfenidone twice daily. These results indicate that the combination of pioglycazone and pamapimod is effective in reducing bleomycin-induced pulmonary fibrosis and is a candidate therapeutic regimen for the treatment of pulmonary fibrosis.

2. Substances and methods:
2.1. Study animals Male C57BL / 6 mice (6-7 weeks old) were used in this study. Animals were weighed one day prior to the start of the study and 60 animals were randomized into 6 groups (N = 10 / group) with similar mean weights to different groups. Food and water were free ingested in a 12 hour light / dark cycle.

2.2. Treatment in study plans groups 2-6 began 1 day prior to bleomycin administration and continued until the end of study on day 21. -On day 1, animals were given vehicle control (0.5% methylcellulose; group 1 and group 2), 25 mg / kg / dose of pioglycazone (group 3), 100 mg / kg / dose of pamapimod (group 4), 25 mg. Pioglycazone at a / kg / dose, 100 mg / kg / dose of pamapimod (group 5), and 100 mg / kg / dose of pyrphenidone (group 6) were administered by gavage and continued for 21 days. Pioglitazone and pamapimod were administered once daily (QD) and pirfenidone was administered twice daily (BID). On day 0, all mice in groups 2-6 received a single injection of bleomycin to induce pulmonary fibrosis. The animals in Group 1 (which received the vehicle from -1 to 21 days) were not infused with bleomycin, but instead received a single dose of saline and were considered sham-negative control mice. Final drug treatment was performed 2-4 hours prior to the end of the study on day 21.

Twenty-one days after infusion of bleomycin, body weight, absolute lung weight, and lung weight normalized to body weight were measured for all mice and compared to bleomycin-injected vehicle-treated control mice. The lobules of the inferior vena cava from the right lung were collected and frozen rapidly. The remaining lungs were fixed in 10% NBF, histopathological analysis was performed, and modified Ashcroft scores were used to assess the severity of fibrosis.

2.3. Compounds and Vehicle Formulas Vehicles (0.5% methylcellulose) and compounds were prepared weekly and stored in the dark at room temperature. From day 1 to the end of the study on day 21, all mice were administered 200 μl volume of vehicle or test compound by gavage by QD or by gavage by gavage 100 μl of pirfenidone by BID. For the group receiving both pirfenidone and the test compound, 100 μl of pirfenidone was administered by BID and the total amount of 100 μl of the test compound was delivered by QD.

2.4. Collection Procedure This study was completed on day 21 for all groups approximately 2-4 hours after final compound or vehicle control treatment. All mice were anesthetized with isoflurane inhalation anesthesia and sacrificed by cervical dislocation.

Lungs were taken from each animal and weighed. The lobules of the inferior vena cava from the right lung were separated by suturing to prevent leakage from the rest of the lung. The lobules of the inferior vena cava were weighed and frozen rapidly for further analysis. The remaining lungs from each animal were inflated with 10% neutral buffered formalin (NBF) and then fixed in 10% NBF for histological examination.

2.5. Fibrosis scoring Lung samples were processed and all lobules from each mouse were embedded in one paraffin block. Coronary sections from the four major leaflets were stained with Masson's trichrome stain. For each animal, continuous lung regions were tested with a raster pattern using a 20X objective and a 10X eyepiece (200X). A modified Ashcroft score (Hubner et al., 2008) was recorded for each region. The fiber index was calculated as the sum of the modified Ashcroft region scores divided by the number of regions tested. The results of microscopic evaluation of histopathology were entered directly into the Excel 2016 spreadsheet.

The 21st day endpoint data is shown as the mean Ashcroft score per experimental group, along with the mean standard error (SEM). Statistical differences between groups (defined as p <0.05) were analyzed using t-test with Prism version 7.0 software (GraphPad, La Jolla, CA). The group treated with the test compound was compared with bleomycin-injected vehicle control-treated mice.

3. 3. Result 3.1. Absolute Lung Weight and Normalized Lung Weight As shown in FIG. 1, bleomycin infusion resulted in a significant increase in post-normalized lung weight compared to sham control without bleomycin infusion. Substantially smaller post-normalized lung weights were observed in groups treated with either 25 mg / kg pioglitazone or 100 mg / kg pamapimod alone or in combination (Groups 3, 4 and 5 vs. Group 2). , P <0.05, t-test). It should be noted that this combination reduced lung weight after normalization to a greater extent than the positive control pirfenidone (Group 6).

3.2. Fibrosis Score As shown in Figure 2, when induced daily with 1.5 U / kg bleomycin followed by a 200 μL vehicle (Group 2), significantly higher fibrosis and the highest group mean fibrosis index (4.8). ) Was brought. Substantially lower fibrosis was present in the group treated with either 25 mg / kg pioglitazone or 100 mg / kg pamapimod alone or in combination, as indicated by the lower mean fibrosis index group (Group 3). 4, 5 pair group 2, P <0.05, t-test). The group with the lowest mean fibrosis index was present in group 5, indicating that the combination of pioglitazone and pamapimod was more effective in lowering the fibrosis score than either drug alone. It should be noted that this combination reduced the post-normalized fibrosis score to a greater extent than the positive control pirfenidone (Group 6).

Example 2
Combination therapy with pamapimod and pioglitazone shows synergistic effects on interleukins and altered gene expression in the TNF pathway in mouse lung tissue. Summary Fibrosis is a pathological process characterized by the replacement of normal tissue with mesenchymal cells and extracellular matrix. The sequence of events leading to pulmonary fibrosis involves inflammation and destruction of normal tissue structures. Some cytokines are involved in local injury and inflammation. These include interleukin-1 (IL-1), interleukin-8 (IL-8), interleukin-6, and tumor necrosis factor-alpha (TNF-alpha) and related molecules. The present inventors performed a whole-genome expression analysis of lung tissue derived from the bleomycin-based fibrosis study presented in Example 1. Unexpectedly, these results revealed that pioglycazone and pamapimod have a synergistic effect that significantly regulates the expression of multiple interleukin / interleukin receptors and TNF / TNF receptor genes. These data suggest that the combination of the two drugs can achieve better therapeutic efficacy than either drug alone in the treatment of pulmonary fibrosis.

2. material and method:
Changes in total gene expression were determined by Illumina next-generation RNA sequencing in lung samples from the animal studies described in Example 1. RNA was extracted from the leaflets of the inferior vena cava that was rapidly frozen at the end of this study. For this analysis, 8 samples (48 samples in total) were analyzed from each of treatment groups 1-6. Briefly, total RNA was extracted using standard methods for next-generation sequencing, and then an Illumina TruSeq RNA library containing poly (A) enrichment was generated. Sequencing was performed using a 30Mio package on NextSeq 500, v2, high output with a read count of 1 × 75 bp. Demultiplexing and trimming of Illumina adapter residues was performed on the raw data. Data reading mappings were made using the reference mouse genome mm10.

For bioinformatics analysis, mean expression levels and standard deviations were determined for each gene in 8 stations per treatment group. Next, a paired comparison between the groups was performed to identify the differentiation-expressing gene. The absolute p-value and the adjusted p-value to correct for the multiplicity of the test were calculated for each pair of analysis. The output value of the data consisted of the top 1000 differentiated expression genes. Genes were considered to be significantly up-regulated or down-regulated if differences in intergroup comparison resulted in adjusted p-value <0.10.

3. 3. Results Table 1 shows that in the case of the three treatment groups, the genes were significantly regulated (adjusted p value <0.10) as compared with the disease group of bleomycin alone. Neither pioglitazone nor pamapimod single treatment significantly regulated the expression of interleukin / interleukin receptors, TNF / TNF receptors or members of the CC and CXX motif chemokine families. Unexpectedly, the combination treatment with pioglitazone / pamapimod significantly suppressed the majority of inflammatory cytokines belonging to these four families. Many of these are involved in the pathogenesis of IPF. These data strongly support the synergistic effect of the combination, indicating that this combination has a potentially strong anti-inflammatory effect that is not exhibited by either drug alone. There is.

Claims (15)

For use in methods of preventing or treating fibrotic disorders or disorders in a subject:
A combination drug comprising (a) a PPAR agonist (b) a p38 kinase inhibitor and optionally (c) one or more pharmaceutically acceptable diluents, additives or carriers. The combination drug for use according to claim 1, wherein the p38 kinase inhibitor inhibits p38-alpha and / or p38-beta. The p38 inhibitor is of formula I or II

[During the ceremony,
Z is N or CH,
W is NR ²
X ^l is O, NR ⁴ (in the formula, R ⁴ is hydrogen or alkyl), S or CR ⁵ R ⁶ (in the formula, R ⁵ and R ⁶ are independently hydrogen or alkyl) or C = O,
X ² is O or NR ⁷ and
Ar ¹ is aryl or heteroaryl and
R ² is hydrogen, alkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, heteroalkylcarbonyl, heteroalkyloxycarbonyl, or -R ^21- R ²² (in the formula, R ²¹ is alkylene or -C (= O)-. And R ²² is alkyl or alkoxy)
R ¹ is hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl-substituted cycloalkyl, hetero-substituted cycloalkyl, heteroalkyl, cyanoalkyl, heterocyclyl, heterocyclylalkyl, R. ^12- SO ₂ -heterocycloamino (in the formula, R ¹² is haloalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl ^{), -Y 1-} C (O) -Y ^2- R ¹¹ (in the formula, Y ¹ and Y ² are independently either absent or alkylene groups, and R ¹¹ is hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino), (heterocyclyl). (Cycloalkyl) alkyl or (heterocyclyl) (heteroaryl) alkyl,
R ³ is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, haloalkyl, heteroalkyl, cyanoalkyl, alkylene-C (O) -R ³¹ (in the formula, R ³¹ is hydrogen, alkyl, hydroxy, Alkoxy, amino, monoalkylamino or dialkylamino), amino, monoalkylamino, dialkylamino or NR ^32- Y ^3- R ³³ (in the formula, Y ³ is -C (O), -C (O). O-, -C (O) NR ³⁴ , S (O) ₂ or S (O) ₂ NR ³⁵ , R ³² , R ³⁴ and R ³⁵ are independently hydrogen or alkyl and R ³³ is , Hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl or optionally substituted phenyl) or acyl,
R ⁷ is hydrogen or alkyl
R ⁸ and R ⁹ are independently hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, alkylsulfonyl, arylsulfonyl, -C (O) -R ^8l (in the formula, R ⁸¹ is , Alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, alkoxy, aryloxy, amino, mono or dialkylamino, arylamino or aryl (alkyl) amino), or R ⁸ and R ⁹ Together form = CR ⁸² R ⁸³ (in the formula, R ⁸² and R ⁸³ are independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl or optionally substituted phenyl). ]
The combination pharmaceutical for use according to claim 1, wherein the compound or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable diluents, additives or carriers. The p38 inhibitor is Formula I

[In the formula, Ar ¹ , W, X ¹ , X ² , Z, R ¹ and R ³ are as defined in claim 3].
The combination drug for use according to claim 3, which is a compound of the above or a pharmaceutically acceptable salt thereof. The p38 kinase inhibitors are pamapimod, akumapimod, rosmapimod, dilmapimod, semapimod, AZD7624, ARRY-371797, LY2228820, R9111, PH-779804, BIRB796, VX-702, VX-745, SB239063, SB239063, SB. The combination drug for use according to claim 1, selected from the group consisting of pharmaceutically acceptable salts thereof. The p38 kinase inhibitor is pamapimod (6- (2,4-difluorophenoxy) -2- [3-hydroxy-1- (2-hydroxyethyl) -propylamino] -8-methyl-8H-pyrido [2, 3-d] Pyrimidine-7-on, formula III),

Alternatively, a combination drug for use according to claim 1, which is a pharmaceutically acceptable salt thereof. The combination drug for use according to any one of claims 1 to 6, wherein the PPAR agonist activates PPAR gamma and / or PPAR alpha. The combination drug for use according to any one of claims 1 to 6, wherein the PPAR agonist activates PPAR gamma. The use according to any one of claims 1 to 6, wherein the PPAR agonist is selected from the group consisting of pioglitazone, rosiglitazone, troglitazone, phenofibrate, bezafibrate and pharmaceutically acceptable salts thereof. Combination drug for. The combination drug for use according to any one of claims 1 to 6, wherein the PPAR agonist is pioglitazone or a pharmaceutically acceptable salt thereof. The combination drug for use according to any one of claims 1 to 10, wherein the combination is orally administered to a subject. The fibrotic disease or disorder is selected from the group consisting of pulmonary fibrosis, liver fibrosis, renal fibrosis, myocardial fibrosis, ocular fibrosis or cutaneous fibrosis, according to any one of claims 1 to 11. A combination drug for the described use. The combination drug for use according to any one of claims 1 to 11, wherein the fibrotic disease or disorder is pulmonary fibrosis. The pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF), familial interstitial pulmonary fibrosis, nonspecific interstitial pneumonia (NSIP), unexplained organizing pneumonia (COP), sarcoidosis, chronic obstruction. The combination drug for use according to claim 13, selected from the group consisting of lung disease (COPD) and asbestos disease. A kit for use in methods of preventing or treating fibrotic disorders or disorders in a subject.
Less than:
(A) PPAR agonist (b) p38 kinase inhibitor, and optionally (c) a combination drug comprising one or more pharmaceutically acceptable diluents, additives or carriers.
Kit, including instructions for using the kit.

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